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Ann Thorac Surg 2007;84:324-338
© 2007 The Society of Thoracic Surgeons

Reviews

Surgical Resection of Pulmonary Metastases From Colorectal Cancer: A Systematic Review of Published Series

Joachim Pfannschmidt, MD, PhD*, Hendrik Dienemann, MD, PhD, Hans Hoffmann, MD, PhD

Department of Thoracic Surgery, University of Heidelberg, Heidelberg, Germany

* Address correspondence to Dr Pfannschmidt, Department of Surgery, Thoraxklinik Heidelberg, Amalienstr. 5, Heidelberg, D-69126, Germany (Email: joachim.pfannschmidt{at}thoraxklinik-heidelberg.de).


   Abstract
Top
 Abstract
Introduction
 Criteria for Selecting Studies
 Results
 Prognostic Factors
 Preoperative Measurements
 Operative and Postoperative...
 Comment
 References
 
The treatment of patients with pulmonary metastases from colorectal cancer continues to evolve. Recently the use of novel agents as a first-line treatment in metastatic colorectal disease has generated cautious optimism in the oncological community. However, pulmonary metastasectomy remains a mainstay in a multidisciplinary concept for a highly selected subset of patients. A selected group of patients with metastases limited to the lungs may benefit from pulmonary metastasectomy with a 5-year survival rate of up to more than 50%. This review evaluates the current status of surgical resection in pulmonary metastases from colorectal cancer, with special emphasis on prognostic factors that influence survival, as well as on surgical approach and lymph node dissection and its impact on the management of patients with metastatic colorectal disease.


   Introduction
Top
 Abstract
 Introduction
Criteria for Selecting Studies
 Results
 Prognostic Factors
 Preoperative Measurements
 Operative and Postoperative...
 Comment
 References
 
Colorectal cancer is the third most common cancer and the second leading cause of cancer-related mortality estimated for 2006 in the United States [1]. More than half of the patients undergoing resection for colorectal cancer can be expected to have recurrence of the disease [2, 3]. The most frequent sites of recurrence are the liver and the lungs. Patients with untreated metastatic disease have a median survival of less than 10 months and a 5-year survival rate of less than 5% [4, 5].

Conventional treatment of stage IV colorectal carcinoma in most patients is palliative but may prolong survival of patients with unresectable disease. Recent schedules combining fluorouracil-based chemotherapy and oxaliplatin or irinotecan have considerably improved the results of systemic chemotherapy in the palliative treatment of patients with metastatic colorectal cancer [6, 7].

With the development of novel chemotherapy and biological agents we have entered into a new era for the treatment of colorectal cancer. Monoclonal antibodies, like bevacizumab and cetuximab, have recently been used in metastatic colorectal cancer. The use of both bevacizumab and cetuximab are augmented by concurrent administration of chemotherapy [8, 9]. Although promising, the use of monoclonal antibodies remains at an early stage. Addressed for hepatic colorectal metastases chemotherapy used in combination with surgery may prolong the time after resection of hepatic metastases, or downsize to resectability patients previously judged inoperable [10]. The role of chemotherapy with surgery in pulmonary metastases has not been defined until now.

Surgery remains the mainstay in treatment for patients with isolated pulmonary metastases according to the National Comprehensive Cancer Network (NCCN): Clinical Practice Guidelines in Oncology [11]. Only patients who met the criteria for potentially curative operation were included. The pre-conditions valid for potentially curative operation were as follows: (1) the metastases seem to be technically resectable, (2) the general and functional risks are tolerable, (3) the primary tumor is controlled, and (4) no extrathoracic lesions are detected (with the exception of hepatic lesions, in which it is possible to completely remove both hepatic and pulmonary metastases).

Although there is a large number of published series reporting the results of surgical resection of lung metastases from colorectal cancer, the effectiveness of such surgery remains unclear. This systematic review has been undertaken to assess the published evidence for the efficacy of pulmonary metastasectomy in patients with colorectal cancer. It focuses on patient selection for surgery by examining potential prognostic factors for long-term survival.


   Criteria for Selecting Studies
Top
 Abstract
 Introduction
 Criteria for Selecting Studies
Results
 Prognostic Factors
 Preoperative Measurements
 Operative and Postoperative...
 Comment
 References
 
No randomized trials comparing surgical resection versus no surgery have ever been conducted; therefore we have attempted to identify all relevant prospective and retrospective studies reporting the outcome of surgical resection with curative intent of colorectal pulmonary metastases. Patients undergoing repeat pulmonary resection and hepatic and pulmonary metastases resection were also included. To ensure that the reviewed surgical series reflected the outcomes for patients treated with modern surgical, anesthetic, and diagnostic care techniques, we have restricted our qualitative analysis to surgical series published between 1995 and December 2006, reporting on patients included in the studies no later than 1980. There should be a reporting of at least 40 patients in each study. Studies were required to follow-up on patients for at least 30 days after operations for inclusion of data for postoperative morbidity and mortality, and for at least 24 months for inclusion of survival data. All eligible English articles in thoracic surgery recruiting adult patients were included in this review. The outcome measures were overall 5-year survival, operative mortality, and postoperative mortality. As all of the eligible published series were retrospective case series, a qualitative summary was produced to identify and describe trends across all studies.

Search Strategy
Studies were identified by searching Pub Med, MEDLINE, and EMBASE, supplemented by a manual search of reference lists of retrieved studies. The following terms and keywords were used: metastases, lung metastases, pulmonary metastases, resection, surgery, colorectal, colon. The search was carried out in stages to achieve the search with the highest likelihood of retrieving all relevant articles [12]. Similar search terms were combined using the Boolean operator "or" to find all abstracts containing information on the subject. These terms were then combined using the Boolean operator "and" to find articles that contained information on all the search terms.

The studies retrieved by the search strategy were reviewed, and relevant studies were selected according to the definitions in the inclusion and exclusion criteria. All references were downloaded to ensure the absence of duplication of references. When a study had generated multiple publications, the most recent study was used to extract data. Data were extracted onto pre-designed data abstraction forms. The following information was extracted from each study: first author, year of publication, study type, study population, population characteristics, number of patients, and key outcomes.


   Results
Top
 Abstract
 Introduction
 Criteria for Selecting Studies
 Results
Prognostic Factors
 Preoperative Measurements
 Operative and Postoperative...
 Comment
 References
 
Twenty published series were eligible and met all the inclusion criteria without multiple publications presenting updated information or data on different aspects of the same patient population. A total of 1,684 patients were reported in 17 different studies [13–29] demonstrating improved survival after resection of colorectal metastases to the lung; reports on 186 patients in three different studies [30–32] specifically addressed the results after resection of colorectal metastases to the liver and lung. All studies presented data on resected patients, whereas some studies distinguished between R0 (no residual disease) (Table 1) and R1/2 resections (histologic involved margins/macroscopic residual disease), many others left this distinction unclear. The distribution of principal confounding factors, such as adjuvant chemotherapy, disease-free interval, and curative surgery were not reported by several studies. Patients were highly selected and the treatment centers were considered highly specialized. In 9 of the studies it was not stated if postoperative mortality was excluded from survival analysis and patients lost to follow-up were not reported or not included in the appropriate analysis [13, 14, 16, 17, 24, 27, 28, 30, 32]. Sixteen studies were conducted in single centers; three were multicenter studies [16, 23, 32] and one was undertaken by two centers [22] (Table 2).


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  		Table 1 Studies Reporting on Patients With R0 Resections
 

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  		Table 2 Studies Reporting on Patients Undergoing Resection Unclear Whether R0 or R1/2
 
The quality of reporting was poor in many studies. Eligibility criteria for surgery or inclusion criteria were reported by all studies. Length of follow-up was not reported by four studies [14, 24, 28, 29].

Postoperative Mortality
Death within 30 days of pulmonary resection was reported by four studies, ranging from 0 to 2.5% of patients. A further nine studies reported perioperative mortality within an undefined time period [15, 18, 20, 22–26, 31]. Cause of perioperative mortality (n = 8) was reported by five studies [15, 20–22, 24]. There were 3 postoperative deaths caused by pulmonary embolism, 3 deaths caused by pneumonia, 1 by non-specified respiratory failure, and 1 by sudden cardiac failure.

For many reasons, there is a specific risk of postoperative complications and mortality in lung metastasis surgery. These risks are difficult to calculate in the majority of patients, and this stems from previous chemotherapy, radiation therapy, or both.

Overall Survival
All studies reported overall survival of 5 years for all patients undergoing resection of pulmonary metastases (median 48%; range, 41.1% to 56%). Studies that did not distinguish between resections being R0 or R1/2, or only presented with combined data for both types of resection, had a median 5-year survival of 52.5% (range, 38.3% to 63.7%). Thirteen studies presented 5-year survival for patients undergoing R0 resections, either for the whole study population or for subgroups of patients (Table 1). Median 5-year survival for R0 resection was 39.6% (range, 24% to 56.0%). Three studies reporting 5-year survival for nonradical resection had a median 5-year survival of 0% (range, 0 to 21%). Three studies [30–32] reporting exclusively on patients who had pulmonary and hepatic resection of colorectal metastases had a median 5-year survival of 31% (range, 30% to 38%). In conclusion, approximately 40% of patients remained alive 5 years after resection.


   Prognostic Factors
Top
 Abstract
 Introduction
 Criteria for Selecting Studies
 Results
 Prognostic Factors
Preoperative Measurements
 Operative and Postoperative...
 Comment
 References
 
Most consistently there were 14 different factors in the categories tested for prognostic relevance in the different studies: patient demographics (ie, age and gender), primary tumor characteristics (ie, TNM, stage, histology, origin), lung metastases (ie, number, size, laterality, type of resection, thoracic lymph node involvement), timing of metastases (ie, disease-free interval), pre-thoracotomy carcinoembryonic antigen (CEA) value, and different histologic patterns of the primary and lung metastases (Table 3).


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  		Table 3 Significant Prognostic Factors After Multivariate Analysis Among Studies
 
Although most were not consistently reported, there were six measurements evaluated by the preoperative work-up that were identified as independent prognostic factors in multivariate analysis. Six prognostic factors were identified as a result of the operation and histologic examination of the resected specimen.


   Preoperative Measurements
Top
 Abstract
 Introduction
 Criteria for Selecting Studies
 Results
 Prognostic Factors
 Preoperative Measurements
Operative and Postoperative...
 Comment
 References
 
Stage of the Primary Colorectal Cancer
The reporting of Union Internationale Contre le Cancer (UICC) stage of the primary colorectal cancer and Duke’s system was variable (Tables 3, 4);Go eleven studies did not report the stage of the disease at all. In four studies [19, 26, 28, 31], patients were staged according to the UICC system (ie, 51 patients had stage I, 107 patients had stage II, 154 had stage III, and 71 had stage IV disease). Of the patients being staged by Duke’s classification [13, 20, 27, 28, 30], 14 patients had Duke’s A stage, 110 had Duke’s B, 160 had Duke’s C, and 43 had Duke’s D. For patients in the different stages, no difference in long-term survival has been proven, besides a single study. Melloni and coworkers [19] have shown that patients with a T1/T2 stage of the primary tumor have a better survival than patients with T3/T4 stage of the primary disease (5-year survival, 63% vs 34%).


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  		Table 4 Clinicopathologic Features
 
Of nine studies that analyzed the stage of the primary tumor as a measurement for long-term survival, only one study confirmed statistical significance.

Distribution
Twelve studies reported on the distribution (either unilateral or bilateral) of lung metastases at the time of surgery (Tables 3, 4). The majority of patients (n = 886) had lesions localized unilaterally in one lung, and 263 patients had bilateral metastases. Unilateral or bilateral distribution of pulmonary metastases could not be proven to be a prognosticator for survival.

Carcinoembryonic Antigen
The pre-thoracotomy serum level of carcinoembryonic antigen (CEA) had been most consistently reported to be a potential prognostic indicator in patients undergoing metastasectomy with this disease (Table 3). In nine studies an elevated CEA level (>5 ng/mL or >10 ng/mL) was a valuable prognostic measurement associated with poor prognosis compared with seven studies in which CEA had no significant prognosticator. Studies by Saito and colleagues [23], Pfannschmidt and colleagues [21], Sakamoto and colleagues [24], Higashiyama and colleagues [13], Lee and colleagues [18], and Rena and colleagues [22] showed that patients with an increased CEA level had a median 5-year survival of 18.9% (range, 0 to 36%), and those with a CEA level in the normal range had a 5-year survival of 59.3% (range, 42.7% to 86.9%).

Disease-Free Interval
The disease-free interval (DFI) between the resection of the primary tumor and pulmonary metastasectomy was reported by 19 studies (Tables 3, 4). Median disease-free survival was between 20.0 and 37.5 months. Only in the study by Rena and colleagues [22], the DFI was found to be a prognostic factor; they reported on patients with a DFI of 0 to 11 months, 12 to 35 months, and more than 35 months. The 5-year DFI-related survival rates were 22.6%, 38.6%, and 55%, respectively. DeMatteo and coworkers [30] reported on a DFI-2 as a prognostic factor for patients with combined liver and lung resection. In this study DFI-2 was defined as the interval between the first and second metastases. He confirmed improved outcomes in patients presenting with metachronous compared with synchronous detection of hepatic and pulmonary lesions. The DFI was extensively studied by nearly all studies of this review, but only two studies reported DFI as an independent prognostic parameter for long-term survival.

Recurrence
Recurrent disease following pulmonary resection was reported by nine studies, however, very vague [13, 16, 18, 19, 22, 27, 29, 30, 32]. In the studies by Rena and colleagues [22], Higashiyama and colleagues [13], Melloni and coworkers [19], and DeMatteo and coworkers [30], patients without evidence of recurrent disease were reported by 36.3%, 38%, 43%, and 30.8%, respectively.


   Operative and Postoperative Measurements
Top
 Abstract
 Introduction
 Criteria for Selecting Studies
 Results
 Prognostic Factors
 Preoperative Measurements
 Operative and Postoperative...
Comment
 References
 
Surgical Approach
Information on the surgical approach was reported in a minority of studies. Seven studies [20–23, 26, 27, 32] reported on bilateral thoracotomies that were performed simultaneously (ie, sternotomy or clamshell). Only in the studies by Pfannschmidt and colleagues [21] and Saito and colleagues [23] were there a significant number of surgical procedures performed bilateral and simultaneously (ie, n = 61 and n = 18, respectively). No significant difference of survival in multivariate analysis was demonstrated between the different surgical approaches.

Surgical Procedures
Of all the surgical procedures (Table 5), the most common thoracic procedure reported in 14 studies was wedge resection or segmentectomy in 804 patients. Lobectomy was performed in 447 patients, and pneumonectomy was required in only 21 patients. Vogelsang and colleagues [26] found that patients (n = 52) undergoing wedge resections seemed to have a better outcome than patients (n = 23) with anatomic lung resections (5-year survival, 39% vs 25%). In the majority of studies (n = 13), the type of lung resection was no prognosticator for survival. In one study [17] the type of lung resection was not reported, and in five studies [16, 19, 22, 29, 31] the number of surgical procedures was stated.


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  		Table 5 Therapy
 
Radicality of Resection
Radical resection of pulmonary metastases has been recommended by a number of surgeons in surgery for lung metastases [33, 34] (Tables 1–3). In six studies only patients with complete surgical resection were analyzed [18, 21, 23, 24, 26, 27]. In a further seven studies radicality was not stated exclusively, but it can be assumed that in most of these studies patients had a complete surgical resection. Of the four studies dealing with patients after complete and incomplete resections, two studies [19, 20] had a significant improved long-term survival after achieving clear surgical margins were found. In three studies with 20 patients having received incomplete resections, radicality of resection was not found to be an independent prognostic factor [13, 22, 28].

Repeat Pulmonary Resection
Although there were 10 studies with 151 patients with repeat pulmonary resections (Table 3), only seven studies [18–21, 23, 24, 29] analyzed patients with repeated resection separately for 5-year survival. The 5-year survival was reported by Saito and colleagues [23], Pfannschmidt and colleagues [21], and Welter and colleagues [29] with a considerable number of patients (ie, 23, 24, and 31 patients, respectively) with a 5-year survival of 24.5%, 54.6%, and 46%, respectively. In the series by Saito and colleagues [23] the median interval between the first and second resection was 14 months (range, 1 to 55 months). McAfee and colleagues [35] found similar results in a 1992 study with a median interval of 17 months in 19 patients having had repeated resections. No study found repeat pulmonary resection for local recurrent disease as an ominous prognostic factor.

Effect of Combined Liver and Lung Resection
Approximately 5% to 10% of patients with colorectal cancer will have both liver and pulmonary metastases [36] (Tables 3, 5). Identifying candidates who are most likely to benefit from surgery remains controversial. Lung metastases, previously believed to be incurable and treated mainly by systemic chemotherapy, may be amenable to curative resection in selected patients [37, 38].

A total of 460 patients were reported in 16 different studies and in three studies with a special focus on the surgical treatment of hepatic and pulmonary metastases from colorectal cancer. The incidence of synchronous metastatic disease (ie, metastasis found either at the time of primary tumor diagnosis or within 3 months of primary tumor resection) was between 6.9% (4 of 58 patients), 14.9% (7 of 47 patients), and 30.8% (25 of 81 patients) in the studies by DeMatteo and coworkers [30], Headrick and coworkers [31], and Kobayashi and coworkers [32]. The disease-free interval (DFI) between the first and second metastases (ie, synchronous versus metachronous disease) pre-thoracotomy serum level of carcinoembryonic antigen and thoracic lymph node involvement were found to be independent prognostic factors in this subset of patients. No significant difference in outcome was observed between patients with and without history of previously resected hepatic metastases at the time of pulmonary resection with 5-year survival rates between 30% and 42%.

Number and Tumor Size
Most patients were selected for pulmonary metastasectomy with a single metastasis. Some authors [14, 16, 28, 29, 32] have shown that patients with single metastases have a better outcome when compared with patients with multiple metastases, but the impact of the number of pulmonary metastases on long-term survival could not be proven by the majority of studies.

Maximum tumor size was analyzed in 14 studies and was not a significant prognostic factor in most studies. Iizasa and colleagues [14] found the maximum tumor size as a continuous variable (5-year survival, <3 cm, 43% versus >3 cm, 32%) and Vogelsang and colleagues [26] established a cut-off value to discriminate between good and poor prognosis by 3.75 cm (5-year survival, 39% vs 23%). (See Tables 3 and 4.)

Thoracic Lymph Node Involvement
Most investigators reported on nodal involvement in the chest. Lymph node examination was not reported in the studies by Vogelsang and colleagues [26], Wang and colleagues [27], Kayser and colleagues [17], Kobayashi and colleagues [32], Lee and colleagues [18], and DeMatteo and coworkers [30]. In 13 studies thoracic lymph node dissection was performed by lymph node sampling or systematic lymph node dissection in a variable number of patients concurrently with pulmonary metastasectomy (Tables 3, 4). In the study by Sakamoto and colleagues [24] and Welter and colleagues [29] lymph node dissection was only performed in the cases of enlarged lymph nodes detected by the surgeon. Mediastinal and pulmonary lymph node involvement was proven to be an ominous prognostic factor only in studies in which nearly all the patients had undergone a systematic mediastinal and hilar lymph node dissection contemporary with pulmonary metastasectomy [16, 21, 23]. The 5-year survival of the group with lymph node involvement was poor at 0 to 33.5% compared with 38.7% to 71% for patients with no thoracic lymph node metastases [13, 14, 21, 23, 29]. Lymph node involvement was no prognosticator for survival in studies in which lymph node dissection was not performed contemporary with all procedures, or lymph node dissection was carried out only in cases when node enlargement was detected by a computed tomographic (CT) chest scan.

Neoadjuvant and Adjuvant Therapy
In studies with patients receiving additional chemotherapy, different treatment protocols have been applied (Tables 3, 5). Thus the relative contribution of pulmonary metastasectomy to overall survival is difficult to determine when systemic chemotherapy has also been used. Neoadjuvant therapy for the primary colorectal tumor was not reported among these studies. Four studies [16, 20, 26, 31] reported on adjuvant chemotherapy after resection of the primary colorectal tumor. Eight studies reported on neoadjuvant or adjuvant therapy with pulmonary metastasectomy; however, in all studies reported, chemotherapy was of no prognostic significance for long-term survival.

Other Factors
In general, patient sex was not a significant prognostic factor (Table 3). Most recently, Iizasa and colleagues [14] reported an age greater than 60 years as an ominous prognostic factor. In the article by Iizasa and colleagues [14], the cause of death was confirmed by telephone contact; thus it can be assumed that it was looked at as a cancer-related death. So far this publication is the only report on age as a prognosticator for survival. Intestinal localization was reported in 18 studies and revealed 871 patients with colon localization and 829 patients with cancer of the distal colon and rectum. Survival rates were reported by Saito and colleagues [23], Pfannschmidt and colleagues [21], Iizasa and colleagues [14], Lee and colleagues [18], and Higashiyama and colleagues [13], with 5-year survival for colon localization between 34.5% and 65.1%, and for rectum localization between 29.5% and 53.3%. In general, intestinal localization was no significant prognosticator for survival. Information on histopathology (differentiation of the primary tumor or metastases), or immunohistochemical analysis was obtained in seven studies [13, 15, 16, 17, 19, 25, 28]. Ike and colleagues [15], and Kanemitsu and colleagues [16] demonstrated 5-year survival at 89.1% in cases of well-differentiated adenocarcinoma. Studies by Melloni and coworkers [19], Shiono and colleagues [25], and Kayser and colleagues [17] were focused on the correlation between histopathologic and immunohistochemical measurements and survival. Kayser and colleagues [17] reported on vascularization properties and features such as Bcl-2 positivity and CEA and galectin-3-associated structural entropy in primary tumor and metastases as independent prognostic factors. Shiono and colleagues [25] analyzed histopathologic features of pulmonary metastases; they revealed the morphologic feature of aerogenous spread with floating cancer cell clusters (ASFC) and vascular invasion at metastatic sites of prognostic significance for survival. Melloni and coworkers [19] found no correlation between microsatellite instability determined by immunohistochemical evaluation of primary tumors and metastases with survival.

In summary, different histopathologic and immunohistochemical measuremtns have been tested for prognostic significance. At present the information at hand should not exclude patients for pulmonary metastasectomy.


   Comment
Top
 Abstract
 Introduction
 Criteria for Selecting Studies
 Results
 Prognostic Factors
 Preoperative Measurements
 Operative and Postoperative...
 Comment
References
 
Resection for pulmonary metastases was first performed in late 1882 by Weinlechner [39] for metastatic rib sarcoma, in which successful resection of the lung and the associated chest wall was performed. The first case series consisted of 24 patients and was published in 1947 by Alexander and Haight [40]. Ten of the patients underwent a pneumonectomy and 12 a lobectomy. From this time to the mid-1960s, resection of lung metastases was performed infrequently and only in highly selected patients. In the 1970s, experience from major thoracic surgical centers suggested a more liberal indication for surgery [38, 41, 42]. The International Registry of Lung metastases was established in 1991 and accrued 5,206 patients of lung metastasectomy [33]. They noted that complete resection, short disease-free interval, and single lesions were favorable measurements for long-term survival. Aberg and colleagues [43] stated that certain factors had to be considered for patient evaluation for pulmonary metastasectomy. The primary tumor must have been removed, no other organ metastases must be found, and there should be an interval between the primary organ resection and the pulmonary resection. For lung metastases of colorectal origin, there are approximately 10% of all patients with clinically isolated metastases to the lung who are candidates for pulmonary metastasectomy [36]. It seems inappropriate to compare survival rates of unresected or unresectable patients with those classified with good functional reserves who are selected to undergo pulmonary resection. Thus it makes it difficult to evaluate the therapeutic effect of pulmonary metastasectomy on long-term survival based on retrospective case series.

The major obstacle regarding treatment of metastatic lesions is the question of how a regional therapy can be beneficial in the management of a systemic-spreading malignant disease. The question of the true clinical value of therapeutic metastasectomy for patients with pulmonary metastases has to be discussed in the light of new clinical trials combining systemic chemotherapy with surgery for metastatic colorectal cancer [44]. Because controlled clinical studies for pulmonary metastasectomy are lacking, we must review retrospective case series. We will discuss controversial issues regarding prognostic measurements and the conduct of therapeutic metastasectomy.

Technical Aspects
Anterior thoracotomy and posteriorlateral thoracotomy has been the approach most commonly used in pulmonary metastasectomy. It offers a reasonable access to all areas of the hemithorax to accomplish wedge resections and anatomic resections under direct vision, concurrently with a systematic mediastinal and hilar lymph node dissection. The inaccessibility to the contralateral thorax for palpation of the lung seems a significant handicap if no bilateral sequential thoracotomy has been planned. Bilateral thoracotomy (ie, sternotomy and clamshell approach) as an approach alternative to lateral thoracotomy may offer less postoperative discomfort; however it can obviate exposure problems in the posterior aspects of the lungs and for systematic mediastinal lymph node dissection.

Landreneau and associates [45] applied video-assisted thoracic surgery (VATS) for resection of pulmonary metastases for colorectal cancer. The VATS approach offered less painful incision and a shorter hospital stay than open thoracotomy. After preoperative assessment by conventional computed tomography, McCormack and colleagues [46], Liu and colleagues [47], and Mutsaerts and colleagues [48] identified the potential problems of missing small metastatic lesions with VATS; missing pulmonary metastases by preoperative CT scan has been demonstrated by Margaritora and colleagues [49], Friedmann and colleagues [50], and van der Veen and colleagues [51]. Van der Veen and coworkers [51] recommended sternotomy for complete surgical clearance in a one-stage procedure in eligible patients. In recent years some authors have favored the VATS approach for resection of lung metastases based on careful patient selection by high resolution spiral CT scans. Lin and colleagues [52] reported on 99 potentially curative resections of lung metastases with long-term survival comparable with historic results by an open approach. Although helical computed tomography has been shown to improve detection of pulmonary nodules compared with conventional computed tomography, there are still limitations in the sensitivity for lesions <6 mm. Studies from Diederich and colleagues [53], Margaritora and colleagues [49], Ambrogi and colleagues [54], and Kayton and colleagues [55] still identified pulmonary metastases by palpation being missed at helical CT scan.

Although the therapeutic effect of extensive mediastinal lymphadenectomy has been the debated issue in pulmonary metastasectomy [56], it has been generally performed in some thoracic surgical centers by open thoracotomy. The feasibility of systematic lymph node dissection by VATS in lung cancer has been proven by several authors [57].

In conclusion, the VATS approach for therapeutic metastasectomy is highly dependent on metastatic size, number of lesions, and location defined by helical computed tomography, and the technical conduct of the VATS approach. To this day, open thoracotomy still remains the most researched surgical approach for pulmonary metastasectomy. However, VATS is now playing an important role for nodules located in the periphery of the lung.

Complete Resection of All Pulmonary Metastases
Microscopically complete surgical resection has been considered to play an important role in the treatment of pulmonary metastases. Nonetheless, there are some patients who may benefit from incomplete resection, because even if they proved to be unresectable in entirety, they had a lesser tumor burden left behind. Metastasectomy as a cytoreductive strategy for treatment of pulmonary metastases in breast cancer has been discussed [58]. To strengthen the need for bi-manual palpation of the lung to determine complete surgical resection, open thoracotomy was advocated but has not shown to improve survival. In the study by Roth and colleagues [59], the finding and removal of contralateral disease in patients preoperatively presumed to have only unilateral disease did not influence survival.

After preoperative assessment of unilateral metastatic disease, many authors make a case for open manual pulmonary examination with the use of unilateral thoracotomy to approach the metastatic lesion and to follow-up the contralateral side by CT scan [60, 61]. The critical question that remains: does missing a small nodule at one operation and resecting it several months later influence survival?

In an attempt to achieve complete surgical resection multiple recurrent thoracotomies for recurrent pulmonary metastases are used. In this subset of highly selectional patients, survival did not differ from survival after complete resection, suggesting that repeated metastasectomy may set the clock back.

Since the 1990s, laser technique was applied for parenchyma-sparing pulmonary resection [62, 63]. In the reviewed articles, the number of pulmonary resections by a laser device was not specifically reported. Recently Rolle and coworkers [64] reported on a kaleidoscope of 328 patients with different primary malignancies (91 patients of colorectal origin) and a total of 3,267 nodules being removed by a new neodymium:yttrium–aluminum–garnett laser device. It seems as though the laser technique potentially increases the number of patients who may be eligible for pulmonary metastasectomy, because the lobectomy rate may be less than what is seen without laser treatment [64].

Survival and Recurrent Disease
Recurrent disease and especially local recurrence after resection of pulmonary metastasectomy was reported vaguely or not at all in many of the reports [13]. Although information on tumor-free survival determines whether survival is related to the pulmonary resection, survival was presented generally as overall survival after pulmonary metastasectomy.

Pulmonary Metastases Tumor Doubling Time
Tumor doubling time was described as an independent prognostic measurement for survival in patients with lung metastases of melanoma [65] and soft tissue sarcoma [66]. Tumor doubling time was not observed in the reviewed articles, although it seems debatable if tumor doubling time may play a role for survival in patients diagnosed with pulmonary metastases of colorectal origin. Chojniak and Younes [67] presented an analysis of growth rate in a patient with pulmonary metastases of different cancer origin by CT scan. In conclusion, it was stated that smaller nodules have a larger tendency to grow, and when they grow they have a smaller mean tumor doubling time. There was an individual and unpredictable growing pattern for every independent lesion.

CEA
Higashiyama and colleagues [13] found that patients with high pre-thoracotomy serum CEA levels showed more frequent post-thoracotomy extrathoracic recurrence, especially in the brain. In several studies the serum CEA level in patients with pulmonary metastases from colorectal cancer is a most important independent prognostic factor. It should be emphasized that patients with elevated pre-thoracotomy serum CEA levels should undergo a careful pre-thoracotomy work-up possibly with positron-emission tomographic examination [68].

Lymph Node Involvement
The presence or absence of lymph node metastasis is discussed as a single important factor for estimating the prognosis in pulmonary metastasectomy for most extrapulmonary malignancies [56, 69–71]. Routine systematic mediastinal and hilar lymph node dissection contemporary with pulmonary metastasectomy has not been uniformly performed in many thoracic surgical centers. Pulmonary metastasectomy systematic lymph node dissection as a standard procedure should be discussed in adoption of the recommended procedures in surgical oncology and especially with lung cancer. In a retrospective study of 28 patients undergoing pulmonary metastasectomy, Kamiyoshihara and colleagues [72] suggested that local recurrence seemed to be decreased when a mediastinal lymph node dissection had been performed. The incidence of thoracic lymph node involvement in metastatic colorectal cancer ranged from 7.1% to 30.3%, and in the large series that included more than 100 patients this range was between 12% and 19.2%.

A report by Pfannschmidt and coworkers [71] specifically addressed the issue of thoracic lymph node involvement in pulmonary metastasectomy. In 245 patients being resected for pulmonary metastases, thoracic lymph node involvement was less often seen in metastatic sarcomas (20.3%) than in metastatic colorectal (31.3%) or renal cell carcinoma (42.4%). For colorectal and renal cell carcinoma, mediastinal lymph node involvement through the spread from abdominal (ie, celiac or portal) lymph node metastases is discussed [73, 74]. In case of pulmonary or hilar lymph node involvement, which is the drainage of the lung, these lymph node metastases are believed to be the result of metastases from the pulmonary metastases [75].

Pastorino and colleagues [76] reported on preoperative mediastinal staging in pulmonary metastatic disease by positron emission tomography in 86 patients. The high frequency of positive extrapulmonary positron emission tomography foci modified the treatment plan in greater than 20% of patients being evaluated for pulmonary metastasectomy.

Although series with lymphadenectomy in pulmonary metastasectomy have demonstrated that metastatically involved lymph nodes adversely affect survival, a positive therapeutic effect of systematic mediastinal and hilar lymph node dissection has not been proven. If pulmonary and lymph node metastases are clinically important because they serve as a source of ongoing disease dissemination, then early removal of such lesions may interrupt the cascade of metastatic cells derived from metastatic sites. Thus surgery may be an important form of systemic therapy [72].

Contribution of Additive Systemic Therapy
Improvements in the systemic therapy of colorectal cancer have markedly changed the prognosis of patients with metastatic disease. Early reports on intensive systemic chemotherapy combined with surgery for pulmonary and hepatic metastatic colorectal cancer have been published [44]. Due to the favorable results in hepatic metastasectomy [77], one may assume comparable results in pulmonary metastasectomy. The application of neoadjuvant systemic therapy has a number of potential advantages in patients with pulmonary metastases. First it helps the selection of systemic agents after resection. The degree of response gives information on the sensitivity of the tumor. Second it may help the selection of candidates for resection by having a short treatment interval, and it may enhance the resectability in some patients [78].

Determination of the role of additive systemic therapy for patients with pulmonary metastases of colorectal origin can only be determined through future prospective trials. At the moment we must carefully individualize the use of neoadjuvant systemic therapy only to those patients with favorable prognostic factors for resection.

Conclusion
The surgical treatment of pulmonary metastases from colorectal cancer is an established technique in the interdisciplinary concept of oncologic therapy. The nature of the published studies on pulmonary metastasectomy for colorectal cancer did not allow for a quantitative analysis to be performed, and therefore we have undertaken a qualitative analysis and review to summarize the available evidence for the effectiveness of this operation.

In summary, there is a substantial body of evidence from retrospective case series demonstrating that resection of colorectal pulmonary metastases can be performed safely with a low mortality rate. For a subset of highly selected patients, the overall results of a 5-year actuarial survival rate ranged between 38.3% and 63.7% (median, 52.5%). These outcomes exceed those normally associated with metastatic colorectal cancer and are well comparable with surgical resection for colorectal liver metastases [79]. The present review was conducted to describe criteria for selecting patients with pulmonary metastases in an attempt to identify patients who would benefit from surgical resection.

Sex, distribution of the pulmonary metastases, repeat pulmonary resection, and additional chemotherapy has not been reported to be significant prognostic factors of survival thus far.

Technical aspects of pulmonary metastasectomy, such as the best surgical approach, the role of minimally invasive techniques, and mediastinal lymphadenectomy are still not clearly determined.

It is commonly stated that radicality is a prognostic factor for long-term survival. Resection of a pulmonary metastasis by taking a circumferentially 0.5 to 1.0 cm margin of normal lung tissue in all directions is recommended [34]. The aim of radicality suggests that neglecting the resection of every abnormal nodule that could possibly be a metastasis exposes the patients to incomplete resection and early death from their malignant disease. The presence of occult metastatic disease seems to be the reason for recurrent pulmonary disease. In this review we found two studies that identified complete surgical resection as a prognosticator, and in three studies this could not be confirmed. In summary, we believe that complete surgical resection is most critical and should be achieved whenever possible.

Mediastinal and hilar lymph node involvement is rarely examined in the literature. Multivariate analysis showed a statistically significant difference in survival between patients with lymph node involvement and those without lymph node metastases. Thus the histologic evaluation of enlarged mediastinal lymph nodes detected in the CT scan by mediastinoscopy (or other invasive diagnostics, eg, transbronchial needle aspiration) has to be discussed prior to pulmonary metastasectomy.

More than 50% of the patients in all of the studies presented with a solitary metastasis. In seven studies, patients with a solitary metastasis demonstrated a significantly better survival compared with patients with multiple nodules. At present it seems that a patient with a solitary metastasis potentially benefits more from pulmonary resection than a patient with multiple pulmonary metastases.

The majority of studies have revealed that an elevated pre-thoracotomy serum CEA level showed a significant adverse effect on survival. Although elevated CEA levels were an ominous prognostic finding, the 5-year survival was still significantly better after pulmonary resection than in patients without surgical resection. Thus patients with an elevated CEA level should not be excluded from pulmonary metastasectomy.

The DFI was shown to be a significant prognostic factor in two studies, but in the majority, the DFI did not affect long-term survival.

At the time of the diagnosis of lung metastases, other metastases (eg, hepatic lesions) are frequently found. As many as 35% of patients presented with hepatic metastases at the time of exploration for resection of primary colon cancer [80].

Several authors reported similar results in survival analysis after pulmonary metastasectomy of patients in the presence of controlled hepatic metastases. Thus we conclude that in selected patients, resection of solitary liver and lung metastases may provide long-term survival. Another interesting result is the finding that 5-year survival of patients may be influenced by histologic characteristics of the primary tumor or metastases, such as histologic differentiation, vascular invasion, ASFC or Bcl-2 +, galectin-3, and CEA-associated structural entropy.

Randomized trials comparing pulmonary metastasectomy versus nonsurgical treatment modalities are not possible now.

To improve the outcome for patients with pulmonary metastatic colorectal cancer, new strategies based on intensive systemic chemotherapy combined with pulmonary metastasectomy should be evaluated in future prospective randomized studies.


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 Abstract
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 Criteria for Selecting Studies
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