The pathophysiology of pulmonary metastases is initiated

Transcription

1 Surgical Management of Pulmonary Metastases Loretta Erhunmwunsee, MD, and Thomas A. D Amico, MD Department of Surgery, Duke University Medical Center, Durham, North Carolina Metastasectomy is the only curative option for some patients with secondary pulmonary malignancy. Many studies suggest a survival benefit in selected patients if complete resection of pulmonary metastases is accomplished. There are several operative approaches that may be used, with the goal of complete resection and with minimal parenchymal loss. Evaluation for resection must include ascertainment of control of the primary tumor and assessment of the ability to achieve complete resection. Minimally invasive approaches may offer advantages in quality of life outcomes, with equivalent oncologic outcomes. (Ann Thorac Surg 2009;88: ) 2009 by The Society of Thoracic Surgeons The pathophysiology of pulmonary metastases is initiated with detachment of cells from the primary tumor and hematogenous dissemination where these cells may arrest in capillary beds. After surviving host defense mechanisms, the tumor cells extravasate into larger arteries and extend into organs by adhering to the basement membrane [1]. Most patients who have pulmonary metastases develop are not curable, owing to presentation with extrathoracic metastases and lack of effective systemic therapy. For some patients with pulmonary metastases isolated to the lungs, resection may improve outcomes. In this review, the operative strategies and outcomes of pulmonary metastasectomy are reviewed, with a focus on patient evaluation, prognostic factors, and surgical strategies. Pulmonary Metastasectomy: Are Outcomes Improved? There are no prospective, randomized trials comparing pulmonary metastasectomy to control, either medical therapy, or observation, yet the resection of pulmonary metastases has gained acceptance in selected patients. Several retrospective studies demonstrate an apparent survival advantage in patients with secondary pulmonary malignancy that undergo complete resection, comparing survival after resection to historical data for unresected patients for whom survival is poor. An important study that assessed the long-term results of pulmonary metastasectomy was based on the International Registry of Lung Metastases [2]. This collaborative project retrospectively reviewed 5,206 cases of lung metastasectomy. Patients with single metastases had a survival of 43% at 5 years, compared with 34% in those with two or three metastases, and 27% in those with four or more metastases. The most important determinant of survival was resectability. The overall 5-year survival for patients who underwent complete resection was 36%, with a median survival of 35 months. In those patients who had undergone incomplete resection, the 5-year survival was only 13%, and the median survival was 15 months [2]. These findings suggest that surgical resection offers a survival advantage for some patients. A prognostic model was created to select those who would benefit most, including the measurements of resectability, disease-free interval (DFI) (more or less than 36 months), and number of metastases (one or multiple). Four distinct prognostic groups were identified: group 1 is the resectable group with no risk factors (DFI [graphic] 36 months and single metastasis); group 2 is the resectable group, with one risk factor (DFI 36 months or multiple metastases); group 3 is the resectable group, with two risk factors (DFI 36 months and multiple metastases); and group 4 is the unresectable group. Median survival was 61 months for group 1, 34 months for group 2, 24 months for group 3, and 14 months for group 4 [2]. In the absence of prospective, randomized trials, it is uncertain whether outcomes of patients with pulmonary metastases are improved by surgical resection. It is possible that the survival of patients with resectable pulmonary metastases is superior to the survival of others, and that resectability itself is the most important prognostic variable, as opposed to resection. Nevertheless, this large registry study establishes the role for pulmonary metastasectomy in selected patients, and numerous subsequent studies support the role of surgical resection. Although it is well-established that the most important prognostic factor related to long-term survival is the ability to achieve complete resection, other issues remain more controversial, including the effects of histology and DFI, as well as surgical technique. Address correspondence to Dr D Amico, Duke University Medical Center, Box 3496, Duke South, White Zone, Room 3589, Durham, NC 27710; damic001@mc.duke.edu. Dr D Amico discloses that he has a financial relationship with Covidien and Scanlan by The Society of Thoracic Surgeons /09/$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg REVIEW ERHUNMWUNSEE AND D AMICO 2009;88: PULMONARY METASTASES 2053 Outcomes According to Histology Colorectal Cancer OUTCOMES. Colorectal cancer is the most common primary histology for patients with potentially resectable pulmonary metastases [2 7]. In a study by Welter and colleagues [3], the outcomes of 175 patients who underwent resection for pulmonary metastases secondary to colorectal cancer were analyzed. They found a 5-year survival of 39% and a median survival of 47.2 months. Rotolo and colleagues [4] analyzed the outcomes of 23 patients after pulmonary resection of single metastases from colorectal cancer, reporting a 5-year survival of 56% and a median survival of 74 months. Lo and colleagues [5] retrospectively evaluated 80 patients who had undergone resection of colorectal carcinoma metastatic to the lungs, with a 5-year survival of 42.5%. PROGNOSTIC FACTORS. In spite of the improved outcomes from pulmonary metastasectomy in some patients with colorectal cancer, the survival of most patients with pulmonary colorectal metastases will not be improved by pulmonary resection. Thus, much focus has gone into determining which patients with colorectal metastases to the lungs should in fact undergo surgery and which patients should not be offered futile resection. Pfannschmidt and colleagues [8] recently reviewed the literature of patients undergoing metastasectomy for colorectal carcinoma, which encompassed 17 studies (1,684 patients) that presented with a 5-year survival for patients undergoing R0 resections [8]. The median 5-year survival for R0 resection was 39.6%. Of nine studies that analyzed the stage of the primary tumor as a measurement for long-term survival, only one study confirmed statistical significance. The majority of patients had lesions localized unilaterally, although neither unilateral nor bilateral distribution of pulmonary metastases could be proven to be a prognosticator for survival. In addition, there was no prognostic value for number of nodules, size of the dominant nodule, DFI, elevated preoperative serum level of carcinoembryonic antigen, use of chemotherapy, or the type of surgical approach used. Finally, there was no study that found repeat pulmonary resection for local recurrent disease was a poor prognostic factor [8]. Onaitis and colleagues [7] also studied the outcomes of 377 patients who underwent complete resection of colorectal metastases to the lungs. In this study, the recurrence-free survival was 28% and overall survival was 78% at 3 years. The authors discovered that DFI less than a year, female gender, and numerous metastases ( 3) were independent significant predictors of recurrence. In addition, 3-year recurrence-free survival was significantly better (49%) for those with only one lesion and a DFI of greater than 1 year [7]. Lo and colleagues [5] suggested that high preoperative carcinoembryonic antigen level ( 20 ug/ml) and short DFI ( 12 months) were negative predictive factors for survival after metastasectomy, whereas the number of pulmonary metastases did not have an affect on outcomes. They conclude that tumors with high-serum carcinoembryonic antigen levels and short DFI are less likely to benefit from pulmonary metastasectomy. PULMONARY METASTASECTOMY IN THE SETTING OF HEPATIC METASTASES. In recent years, the selection criteria for pulmonary metastasectomy have expanded to include patients with limited hepatic metastases. There has been no reported difference in outcome in patients with and without history of previously resected hepatic metastases at the time of pulmonary resection, and thus many perform pulmonary metastasectomy even in patients who have undergone hepatic resection for colorectal metastases at an earlier stage [6 8]. Patients who undergo combination hepatic and pulmonary metastasectomy have a 30% 5-year survival rate [6]. Pfannschmidt and colleagues [8] found similar results with no significant difference in outcome 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% [8]. Review of these studies demonstrates that there is not yet a consensus as to which prognostic factors should be used to determine operability. Well-designed clinical trials must be performed to determine exactly which variables should be focused on in consideration for resection. In the meantime, thoracic surgeons and medical oncologists should work together in deciding which patients are surgical candidates. According to National Comprehensive Cancer Network guidelines, the current criteria for resectability of colorectal metastases to the lungs are: (1) the primary tumor must have been resected for cure; (2) complete resection of pulmonary metastases with maintenance of adequate function must be feasible; (3) resectable extrapulmonary metastases do not preclude resection; and (4) re-resection can be considered in selected patients [9]. LYMPH NODE INVOLVEMENT. The review by Pfannschmidt and colleagues revealed that mediastinal and pulmonary lymph node involvement was an ominous prognostic factor only in studies in which nearly all the patients had undergone a systematic mediastinal and hilar lymph node dissection concurrent with pulmonary metastasectomy [8]. The 5-year survival of the group with lymph node involvement was 0 to 33.5%, compared with 38.7% to 71% for patients with no thoracic lymph node metastases. Lymph node involvement did not predict survival in studies in which lymph node dissection was not performed contemporary with all procedures, or in studies in which lymph node dissection was carried out only in cases when node enlargement was detected by computed tomographic scan [8]. Casali and colleagues [10] performed mediastinal exploration with lymph node sampling in each of 142 patients and detected a survival difference based on the presence of metastases in mediastinal nodes [10]. These authors suggest that nodal status should be considered in the selection of patients for lung metastasectomy [10]. Ercan and colleagues [11] evaluated 70 patients who underwent pulmonary metastasectomy and complete mediastinal lymph node dissection. The 3-year survival

3 2054 REVIEW ERHUNMWUNSEE AND D AMICO Ann Thorac Surg PULMONARY METASTASES 2009;88: for patients with negative lymph nodes was 69% as compared with only 38% for those with positive lymph nodes (p 0.001). Saito and colleagues [12] also reported worse outcomes with patients who had hilar or mediastinal lymph node metastasis. Dominguez-Ventura and colleagues [13] went on to suggest that a complete mediastinal lymphadenectomy be performed for all patients undergoing pulmonary metastasectomy, to better define a patient s prognosis and to guide adjuvant therapy. As these previously mentioned studies suggest, lymph node involvement is likely a negative prognostic factor, but debate still arises concerning which patients should be offered surgical exploration for resection in the setting of clinical nodal involvement. Based on the evidence of negative prognostic value, biopsy or resection of mediastinal or hilar lymph nodes would provide valuable information to guide further decision making. Soft-Tissue Sarcoma After colorectal cancer, sarcoma is the second most frequent source of metastases to the lungs. Frequently the lungs are the only site of metastases from sarcomatous disease. Many studies have suggested survival benefit in those who undergo pulmonary metastasectomy for soft tissue sarcoma [14]. Suri and colleagues [15] evaluated 103 patients with metastatic malignant fibrous histiocytoma to the lungs. They accomplished complete resection in 90% of the patients, and their patients experienced few complications (11%). The 5-year survival in this series was 21%. This study also found that extrapulmonary disease at the time of metastasectomy ( 2 nodules resected) and adjuvant therapy after metastasectomy were associated with decreased survival [15]. Gadd and colleagues [16] studied 135 patients with pulmonary metastases from extremity soft tissue sarcoma. They found that the 3-year survival was 23% after complete resection and only 2% in those treated nonsurgically. They determined factors that were associated with an increased risk of pulmonary metastases: high tumor grade, tumor ( 5 cm), lower extremity site, and histologic type [16]. van Geel and colleagues [17] evaluated 255 patients who underwent complete resection of lung metastases from soft tissue sarcomas [17]. Their 3-year and 5-year overall survival rates were 54% and 38%, respectively. They also found that clear margins (age 40 years) and grades I and II tumors had independent positive influence on survival [17]. Others have also found a survival benefit with resection of soft tissue pulmonary metastases [18, 19], and some have determined that resection of pulmonary metastases from soft-tissue sarcoma is cost-effective [20]. Evidence suggests that the survival benefit is present in children as well. Temeck and colleagues [21] investigated the efficacy of pulmonary metastasectomy in children with sarcoma [21]. In this study, 152 patients underwent 258 thoracic resections. Nearly 100% of their patients underwent chemotherapy and radiation therapy, and many had more than one resection. The median survival was 2.2 years, and the operative mortality was 1.3%. The authors suggest that those who benefit most from surgical metastasectomy are those with a long DFI and a long doubling time [21]. Osteogenic Sarcoma Surgical resection of pulmonary metastases from osteogenic sarcoma is also well accepted and can be considered the prototype for the strategy of pulmonary metastasectomy as follows: there is rarely extrapulmonary metastatic disease, the lesions are easily identified, and there are no effective systemic therapies [21]. In addition, the survival is superior to other histologies, including soft tissue sarcomas [21 23]. Beattie and colleagues [22] performed a complete resection of multiple pulmonary metastases on 22 children with primary osteogenic sarcoma. Follow-up found 6 children alive at 10 years and 5 at 15 years. They concluded that long-term survival is possible in patients who undergo pulmonary metastasectomy for osteogenic sarcoma [22]. Briccoli and colleagues [23] evaluated 94 patients who underwent repeat pulmonary metastasectomy for osteosarcoma spread to the lung. They found that the 3-year and 5-year event-free survival from the first metastasectomy was 45% and 38%, respectively, and 33% and 32%, respectively from the second one [23]. These authors suggest that repeat pulmonary metastasectomy of osteogenic sarcoma is a safe and viable option. Renal Cell Carcinoma Evidence reveals that patients with pulmonary metastases of renal cell carcinoma have a survival benefit after a metastasectomy. Murthy and colleagues [24] studied 92 patients who underwent pulmonary metastasectomy secondary to renal cell cancer metastases. The authors obtained complete resection in 68% of the patients. They observed a 5-year survival of 45% in patients with complete resection, compared with only 8% in those who were incompletely resected. Pfannschmidt and colleagues [25] also evaluated 191 patients who underwent surgical resection from pulmonary metastases from renal cell carcinoma. They achieved complete resection in 149 of those patients. The 5-year survival rate after complete metastasectomy was 41.5%, whereas it was only 22.1% when the resection was incomplete. Those without lymph node involvement had a 5-year survival of 42.1%, and those with lymph node involvement had a 5-year survival of 24.4%. Patients with a longer DFI ( 23 months) had a higher 5-year survival (47%) when compared with those who had a complete resection, but a DFI 23 months (24.7%) [25]. Assouad and colleagues [26] recently found similar results in their evaluation of 65 patients with renal cell pulmonary metastases. Their 5-year overall survival in those who underwent complete resection was 37.2%. They also found that mass size and lymph node involvement were important prognostic factors [26]. Melanoma Petersen and colleagues [27] have reported the survival benefits after the resection of lung metastases from melanoma. They analyzed 1,720 patients with melanoma

4 Ann Thorac Surg REVIEW ERHUNMWUNSEE AND D AMICO 2009;88: PULMONARY METASTASES 2055 with pulmonary metastases and found that patients with complete resection had a median survival of 19 months and a 5-year survival of 21%; these outcomes compared favorably with patients who had incomplete resections, with a median survival of 11 months and a 5-year survival of only 13% [27]. Other Histologies Pulmonary metastasectomy may be considered for patients with primary tumors of other histologic types, such as breast cancer [28], uterine cancer [29], and prostate cancer [30], although patients with these malignancies are less likely to meet the criteria for operability. Summary The histology of the primary tumor is an important factor regarding tumor biology in predicting whether a metastasectomy will improve the outcome of an individual patient. Nevertheless, the histology of the tumor does not determine operability, if the standard operative criteria as described are met. Similarly, numerous prognostic factors, such as DFI, number of metastatic nodules, size of the largest nodule, and lymph node involvement, have been studied extensively, but there is not a consensus as to how these should be used for patient selection. Furthermore, the integration of systemic targeted therapy, such as bevacizumab for colorectal cancer or sunitinib for renal cell carcinoma, should be considered in decision making regarding candidacy and timing for surgery. Preoperative Evaluation In general, to be considered for pulmonary metastasectomy patients must fit the following criteria: the primary disease is controlled (or controllable); there is no other distant disease; complete resection of pulmonary involvement is achievable with adequate pulmonary reserve; and there are no effective medical therapies. Control of the Primary Tumor For pulmonary metastasectomy to have survival value, the primary tumor itself must be controlled or controllable. If the pulmonary metastases are recognized metachronously, the site of the primary tumor is examined to exclude local recurrence. For example, in patients with colorectal cancer, a colonoscopy is performed. If the pulmonary disease has presented synchronously, the primary tumor is assessed and a decision is made regarding management. If no other metastatic disease is present, staged resection of the primary tumor and the pulmonary nodules is a reasonable approach if complete resection can be achieved. Ability to Achieve Complete Resection With Adequate Pulmonary Reserve Assessment of the ability to achieve complete resection with adequate pulmonary reserve includes appraisal of the number of nodules, consideration of the location of nodules, and estimation of the postoperative pulmonary function. For patients with unilateral involvement of three or fewer nodules and preserved pulmonary function (forced expiratory volume in 1 second 80%), the assessment is straightforward. For patients with bilateral involvement of five or more nodules, the calculation is more difficult, especially if any of the lesions are central and require anatomic resection. There is no consensus regarding the number of nodules and the ability to achieve complete resection. In patients with bilateral lesions who are potentially unresectable, median sternotomy or bilateral transsternal thoracotomy may be used to simultaneously evaluate both lungs to judge resectability. Assessment of the Number of Nodules With Computed Tomography The ability to achieve complete resection is considered integral to achieving the potential survival benefit of metastasectomy. The computed tomographic (CT) scan of the chest is regarded as the most important preoperative radiologic examination, but its ability to detect all metastatic nodules is uncertain. Thus, surgeons also rely on manual palpation to locate nodules that may escape CT detection. McCormack and colleagues [31] prospectively studied the usefulness of video-assisted thoracoscopic surgery (VATS) versus thoracotomy for metastasectomy in 50 patients with nodules suspected to be pulmonary metastases on CT scan [31]. They performed thoracoscopic resection of nodules identified on the CT scan and then proceeded with an open thoracotomy with bi-manual palpation to find and resect undetected lesions. Of the first 18 patients, 10 were found to have malignant lesions that were missed by CT and VATS. The authors concluded that the CT scan would fail to detect all nodules, and therefore that the VATS for a metastasectomy would not result in complete resection [31]. Parsons and colleagues [32] compared the number of nodules identified on the preoperative helical CT scans of 53 patients to their respective pathologic report after resection and found CT detected approximately 55% of the nodules. The preoperative CT was entirely correct in only 19% of patients. The authors suggested that because of the high inaccuracy rate of the detection of pulmonary metastases by CT, bi-manual palpation of lungs for detection of those lesions missed on CT must be performed [32]. Whereas single-detector row helical CT scans produce 3-mm to 5-mm thick image reconstruction, thin-slice multi-detector row CT scanners allowed the entire lung to be scanned with 1-mm sections in as little as 5 seconds [33]. Kang and colleagues [33] used the thin slice 16- detector row CT scan preoperatively in 27 patients and compared the findings to the pathology report after resection. In nonosteosarcoma patients, the CT found 67 of 69 metastatic nodules detected by bi-manual palpation intraoperatively. Exclusion of Extrathoracic Disease Staging for distant metastatic disease is performed prior to pulmonary resection, based on the primary tumor. In most patients, CT of the chest and abdomen was per-

5 2056 REVIEW ERHUNMWUNSEE AND D AMICO Ann Thorac Surg PULMONARY METASTASES 2009;88: formed to exclude liver metastases. For patients with sarcoma, the positron emission tomographic (PET) scan or bone scan may be performed to assess for the presence of bone metastases [14]. The PET scan is also commonly used to assess metastatic disease in patients with epithelial tumors and melanoma, but the effectiveness of PET is questionable [9, 34]. In a series by Fortes and colleagues [34], the sensitivity of PET was evaluated in a series of 83 patients who underwent a pulmonary metastasectomy [34]. In this series, the PET scan was positive in only 67.5% of the malignant nodules (colon, 68.6%; renal cell carcinoma, 71.4%; sarcoma, 44.4%), which casts doubt on the ability of the PET scan to identify extrathoracic metastatic disease. Any patient with pulmonary metastases who presents with neurologic symptoms should undergo a brain magnetic resonance image to exclude involvement of the central nervous system. Summary Preoperative evaluation must focus on the two most critical issues: (1) exclusion of extrathoracic disease and (2) attaining complete resection. Distant metastatic staging may vary by histology, and the use of the PET scan is not established or reliable for all histologies. In addition, staging should include ascertaining control of the primary tumor, even in cases of metachronous presentation and long DFI. There is no consensus on what constitutes operability in terms of number of nodules. It must be recognized that complete resection is more difficult, as with increasing number of nodules, especially if one or more of the nodules is central in location. The reliance on CT scanning to identify all pulmonary metastases has been criticized, but the latest generation of CT scanners is superior to those used in previous studies. Although it is probable that CT scanning alone will not detect all pulmonary nodules in every patient, there is no evidence that manual palpation improves the overall efficacy of pulmonary metastasectomy. However, the use of thoracoscopy versus thoracotomy is still considered controversial. Surgical Resection Extent of Surgical Resection Most pulmonary metastases are located peripherally and are frequently immediately subpleural, amenable to a wedge resection. When metastatic disease is more central, the anatomic resection (ie, segmentectomy, lobectomy, bilobectomy, or pneumonectomy) may be performed with effort to preserve as much pulmonary parenchyma as possible. Of the 5,206 patients that were analyzed in the International Registry of Lung Metastases, 67% underwent a wedge resection, 9% a segmentectomy, 21% a lobectomy or bilobectomy, and 3% underwent a pneumonectomy [2]. It appears that wedge resection, if feasible, is as effective as anatomic resection. Pfannschmidt and colleagues [8] performed a systematic review of 20 studies that focused on the outcomes of pulmonary metastasectomy from a colon cancer primary, which suggested that the extent of resection was not an important prognostic factor for survival. These results support the practice of performing limited resection when possible to preserve lung parenchyma and function while achieving clear margins. Surgical Approaches in Pulmonary Metastasectomy The goals of surgery in patients with secondary lung malignancy include achieving complete resection when possible, conserving pulmonary parenchyma, and identifying patients in whom a resection would be futile, such as when complete resection is not possible or when radiographic evaluation underestimates the extent of disease. Although there are no prospective studies evaluating quality of life after metastasectomy, lung conservation should be considered essential. Potential surgical approaches to pulmonary metastasectomy include thoracotomy, thoracoscopy, thoracoscopy with subxiphoid manual palpation, median sternotomy, bilateral synchronous thoracotomies, and bilateral trans-sternal thoracotomy. In the International Registry, the surgical approach was unilateral thoracotomy in 58%, bilateral synchronous or staged thoracotomy in 11%, median sternotomy in 27%, and thoracoscopy in 2% [2]. Open Approaches Conventional open surgical approaches include thoracotomy, sternotomy, and bilateral trans-sternal thoracotomy (clamshell). The most frequently used approach is the posterolateral thoracotomy, which provides excellent exposure and the ability to palpate the lung for lesions not detected radiographically. The drawbacks of thoracotomy include postoperative pain and the inability to perform bilateral resection under one general anesthetic in most patients. Median sternotomy offers the advantage of assessing both lungs prior to resection and achieving bilateral resection, with less postoperative pain compared with bilateral thoracotomy (staged or simultaneous). However, a sternotomy provides suboptimal exposure of the posterior lung fields, and it is inadequate for sublobar anatomic resection of the lower lobes in most patients. Finally, a bilateral trans-sternal thoracotomy, also termed clamshell approach, can be used. This approach provides excellent bilateral exposure of all lung fields and adequate exposure for any anatomic resection. The disadvantages of this approach include acute and chronic postoperative pain, and the sacrifice of both internal mammary arteries. Most patients considered for resection for metastatic disease have bilateral involvement [35]. Roth and colleagues [35] studied outcomes in matched patients with unilateral metastases from extremity soft-tissue sarcomas diagnosed on CT scan. They compared patients who underwent metastasectomy by a thoracotomy to those who underwent median sternotomy for their unilateral disease, and they found that there was no difference in survival. They concluded that neither the type of incision nor the use of bilateral bimanual palpation influenced outcomes [35]. Although the achievement of complete

6 Ann Thorac Surg REVIEW ERHUNMWUNSEE AND D AMICO 2009;88: PULMONARY METASTASES 2057 resection is the most important prognostic variable associated with survival, there is no evidence that the use of staged bilateral resection is inferior to a single bilateral approach. Thoracoscopic Approach Potential advantages of the minimally invasive approach include smaller incisions, less postoperative pain, shorter length of stay, fewer adhesions at reoperation, and better compliance with adjuvant therapies if indicated [36 41]. The argument against the minimally invasive approach is that small ( 5 mm) malignant nodules may be missed without the benefit of bi-manual palpation [31, 32, 42]. However, the biology of pulmonary metastases may, in fact, support the use of thoracoscopic resection [43]. First, any resected metastatic disease was present (at least microscopically) prior to the treatment of the primary lesion, and has been missed for a significant period of time. There is no evidence to suggest that the timing of resection of nodules that would be missed at thoracoscopic resection, which are usually 5 mm in diameter, is critical to the final outcome. Second, multiple resections do not adversely affect the overall outcome of patients with metachronously detected metastases. Third, patients who subsequently have unresectable disease develop will not have benefited from thoracotomy. Fourth, resection may be less stressful for patients, and therefore result in less immunosuppression, resulting in a more favorable disease course. Currently, there is no evidence that resection of pulmonary metastases at the time that they become radiographically apparent is any less efficacious than open procedures that remove all nodules, benign and malignant, before their radiologic identification. Gossot and colleagues [44] recently revealed that patients with sarcomatous pulmonary metastases had favorable long-term survival after thoracoscopic resection [44]. In this study, 31 patients who underwent thoracoscopic resection had similar 1-year, 3-year, and 5-year overall and disease-free survivals when compared with the 29 matched controls who underwent thoracotomy resection. Both groups had 36% to 41% repeat resections. The authors also suggested that thoracoscopic approach is viable in those with two or fewer nodules, favoring peripheral subpleural location [44]. Several other recent studies suggest that VATS resection of pulmonary metastases yields comparable survival to thoracotomy. Nakajima [45] studied 143 patients with pulmonary metastases secondary to colorectal cancer who were diagnosed by helical CT scan. In this study, 71 patients underwent open thoracotomy, whereas 72 patients underwent VATS; 22 patients in the open group and 21 patients in the VATS group had multiple lesions. The authors reported superior 5-year survival (49.3%) in the VATS group compared with 39.5% in the open group (p 0.047). The 5-year disease-free survival was 34.4% for the VATS group and 21.1% for the open group (p 0.064). Although the thoracoscopic group had a higher fraction of those with smaller diameter lesions, fewer lesions, and those with lesions located more peripherally, there was no evidence of deleterious outcomes in patients who underwent VATS metastasectomy. The authors suggest that VATS metastasectomy is a safe and valuable alternative to the open thoracotomy in selected patients [45]. Another recent study analyzed outcomes of 35 patients with previous extrathoracic malignancy. Each patient had a solitary nodule ( 3 cm in diameter) that was suspicious for metastasis [46]. The VATS metastasectomy with (n 19) or without (n 16) confirmatory thoracotomy was performed. Of these 35 patients, 15 had nodules that were not metastases, including seven benign nodules and eight primary lung cancers. Among the other 20 patients with pulmonary metastatic disease, there was no difference in overall or disease-free survival between those that did and did not have a thoracotomy performed after VATS. The authors conclude that thoracoscopic resection of solitary peripherally located metastases is a safe and potentially curative procedure with a long-term outcome that is comparable with that after resection by thoracotomy [46]. A modification of the thoracoscopic technique includes the use of a subxiphoid incision with transxiphoid assistance [47, 48]. This technique combines the advantages of minimally invasive surgery with the assurance of manual palpation. In a recent series, 65 patients with pulmonary metastases were bilaterally explored; of the 65, 44 were without radiologic evidence of contralateral lesions. Transxiphoid palpation identified 23 occult metastases in 10 of the 65 patients. Multiple Procedures The use of multiple pulmonary resections for recurrent disease has also been studied in patients who develop pulmonary metastases in the absence of extrathoracic disease. Welter and colleagues [3] found that repeat resections of pulmonary metastases secondary to colorectal cancer was safe and provided long-term survival, which may be required even if the first resection was by thoracotomy. The authors reported 5-year survival of 53.8% in those who had repeat resection of pulmonary metastases. This study suggests that metastasectomy can be performed once the lesions grow and are detectable with good outcomes. Kandioler and colleagues [49] evaluated 330 patients who had undergone at least two complete surgical procedures because of recurrent metastatic pulmonary disease. They found 5-year and 10- year survival rates after the first metastasectomy to be 48% and 28%, respectively. These authors go on to suggest that patients who are persistently free of disease at the primary location, but who have recurrent, resectable metastatic disease of the lung, are likely to benefit from operations for a second, third, or even fourth time [49]. The outcome of patients who underwent a second metastasectomy in the International Registry was excellent. The 5-year and 10-year survival was 44% and 29%, respectively, compared with 34% and 25%, respectively, for patients having had one operation [2]. The favorable long-term results suggest a curative benefit of repeated

7 2058 REVIEW ERHUNMWUNSEE AND D AMICO Ann Thorac Surg PULMONARY METASTASES 2009;88: salvage operations, rather than a simple selection effect, with no apparent disadvantages. These results suggest that the biology of the tumor is more important than the strategy of resection. Some lesions that are not detected by CT scan may be removed once they are detected at a later date without negatively influencing survival, because their biology is less aggressive; whereas resection of every possible lesion in a patient with very aggressive tumor biology may still lead to poor survival. Summary It appears that thoracoscopic resection is a viable option for resection of pulmonary metastases in selected patients, especially in those with three or fewer nodules. In review, the success of the thoracoscopic strategy is based on several factors. First, there is no evidence that the achievement of a complete resection by a second operation results in inferior outcome. Second, many curable patients require multiple operations in any case, and sequential minimally invasive procedures certainly represent an advantage over sequential thoracotomies. Finally, many patients are not curable and develop systemic metastases subsequent to pulmonary resection; none of these patients benefit from a thoracotomy whose only potential advantage would be to identify and resect nodules less than 5 mm in diameter. However, the use of thoracotomy versus thoracoscopy for pulmonary metastasectomy has not been studied prospectively, and the advantages and disadvantages of each technique should be weighed in making a decision for each patient. Alternative Treatment Options Isolated Lung Perfusion Although surgical resection is effective in some patients with metastatic disease in the lung, the majority of patients with pulmonary metastases develop unresectable disease. In addition, some patients present with disease not amenable to resection. The concept of isolated lung perfusion has been developed to treat unresectable disease. Isolated lung perfusion involves direct infusion of chemotherapeutic drugs into the affected lung, allowing higher doses of agents to be infused locally, without the systemic side effects that would accompany such doses. van Putte and colleagues [50] have studied this concept in rats and have found a survival benefit with the infusion of gemcitabine and melphalan through the isolated lung perfusion technique. Gemcitabine is a deoxycytidine analog that is phosphorylated and incorporated into the DNA once entering the cell, whereas melphalan is an alkylating agent that results in DNA interstrand or DNA protein cross links that cause inhibition of DNA synthesis. Left pulmonary metastases were induced in Wag/Rij rats by means of intravenous injection of CC531s adenocarcinoma cells. On day 7, the rats underwent left isolated lung perfusion with different monotherapy or drug combinations. The in vivo treated rats lived longer compared with the control animals (p ). The combination of melphalan-gemcitabine resulted in 67% survival of the rats after 90 days versus 0% in other groups [50]. Animal studies of isolated lung perfusion have shown promise, and phase I clinical trials in humans have been performed as well, which show that isolated lung perfusion metastasectomy are feasible [51]. Different drugs have been used including doxorubicin, cisplatin, tumor necrosis factor-alpha, interferon-gamma, and melphalan as monotherapy or in combination. Most studies reveal that this procedure is well tolerated and that significant drug levels are obtained in pulmonary metastases and lymph nodes without systemic toxicity [51]. A phase II clinical trial by Van Schil and colleagues will be initiated soon in patients with resectable lung metastases from colorectal adenocarcinoma, soft tissue, and osteosarcoma [52]. Ablation Techniques Several new options are being studied to treat patients who have a limited number of pulmonary metastases that are not operable based on medical issues, such as cardiac status. Stereotactic radiosurgery is one option for ablation, and this technique may involve image-guided robotics (Cyberknife; Accuray, Sunnyvale, CA). The Cyberknife was been examined in 35 patients with lung metastases in one study [53]. Of the 35 patients, 77% were alive at a median of 18 months. The authors concluded that the Cyberknife achieves good rates of local disease control with limited toxicity to surrounding tissues, and that the technique may be beneficial for patients for whom surgery is not an option [53]. Although this radiation technique is more commonly used for patients with primary lung cancer, the efficacy of stereotactic radiosurgery and the Cyberknife in patients with multiple nodules is currently under investigation. Human and animal studies support the use of radiofrequency ablation for pulmonary malignancies, including metastases. King and colleagues [54] studied 20 patients with 44 lung metastases secondary to colorectal cancer who were treated with radiofrequency ablation. The authors found that 6 months after treatment, the CT scan demonstrated that 3 lesions had progressed, 25 metastases were stable or smaller, and 11 were no longer visible. At 12 months 5 metastases had progressed, 11 were smaller or stable, and 9 were not visible [54]. Comment Metastases to lungs are common in patients with malignancy, and isolated pulmonary metastases may be seen in patients with many types of cancer. It seems highly likely that pulmonary metastasectomy does improve outcomes in appropriately selected patients. Selection criteria include established control of the primary tumor, an absence of extrathoracic involvement, and disease amenable to complete resection with adequate residual pulmonary reserve. Many studies have investigated prognostic factors related to pulmonary metastasectomy, including number of nodules, size of the dominant nodule, ability to achieve

8 Ann Thorac Surg REVIEW ERHUNMWUNSEE AND D AMICO 2009;88: PULMONARY METASTASES 2059 complete resection, histology, and disease-free interval. Although each of these factors may influence outcome, the most important determinant of long-term survival is achieving a complete resection. To optimize postoperative pulmonary function, parenchymal-sparing techniques are used whenever possible. Wedge resection is the most common surgical procedure, but more central lesions may require segmentectomy, lobectomy, and (rarely) pneumonectomy. Although posterolateral thoracotomy with manual palpation is considered important to identify all nodules and achieve complete resection, many surgeons prefer thoracoscopic resection. In addition to advantages in quality of life outcomes, the thoracoscopic strategy also simplifies reoperation when necessary and may prevent futile thoracotomy. Although complete resection is essential to improve survival, it is possible that staged complete resection is equally effective. References 1. Khokha R, Voura E, Hill RP. Tumor progression and metastasis: cellular, molecular, and microenvironmental factors. In: The Basic Science of Oncology. McGraw-Hill 4th ed, Pastorino U, Buyse M, Friedel G, et al. Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. J Thorac Cardiovasc Surg 1997;113: Welter S, Jacobs J, Krbek T, et al. Long-term survival after repeated resection of pulmonary metastases from colorectal cancer. Ann Thorac Surg 2007;84: Rotolo N, De Monte L, Imperatori A, et al. Pulmonary resections of single metastases from colorectal cancer. Surg Oncol 2007;16: Lo C, Chu C, Zhu T, et al. Pulmonary resection for metastases from colorectal cancer. Surgical Practice 2007;11: Joosten J, Bertholet J, Keemers-Gels M, et al. Pulmonary resection of colorectal metastases in patients with or without a history of hepatic metastases. Eur J Surg Oncol 2008;34: Onaitis MO, Petersen RP, Haney JC, et al. Prognostic factors for recurrence after pulmonary resection of colorectal cancer metastases. Ann Thorac Surg 2009;87: 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: National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology: Colon and Rectal Cancer Last accessed May 16, Casali C, Stefani A, Storelli E, et al. Prognostic factors and survival after resection of lung metastases from epithelial tumors. Interact Cardiovasc Thorac Surg 2006;5: Ercan S, Nichols FC, Trastek VF, Deschamps C, et al. Prognostic significance of lymph node metastasis found during pulmonary metastasectomy for extrapulmonary carcinoma. Ann Thorac Surg 2004;77: Saito Y, Omiya H, Kohno K, et al. Pulmonary metastasectomy for 165 patients with colorectal carcinoma: a prognostic assessment. J Thorac Cardiovasc Surg 2002;124: Dominguez-Ventura A, Nichols FC. Lymphadenectomy in metastasectomy. Thorac Surg Clin 2006;16: National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma. Last accessed May 16, Suri RM, Deschamps C, Cassivi SD, et al. Pulmonary resection for metastatic malignant fibrous histiocytoma: an analysis of prognostic factors. Ann Thorac Surg 2005;80: Gadd MA, Casper ES, Woodruff JM, McCormack PM, Brennan MF. Development and treatment of pulmonary metastases in adult patients with extremity soft tissue sarcoma. Ann Surg 1993;218: van Geel AN, Pastorino U, Jauch KW, et al. Surgical treatment of lung metastases The European Organization for research and treatment of cancer-soft tissue and bone sarcoma group study of 255 patients. Cancer 1996;77: Casson AG, Putnam JB, Natarajan G, et al. Five-year survival after pulmonary metastasectomy for adult soft tissue sarcoma Cancer 1992;69: Pastorino U, Valente M, Gasparini M, et al. Median sternotomy and multiple lung resections for metastatic sarcomas. Eur J Cardiothorac Surg 1990;4: Porter GA, Cantor SB, Walsh GL, Rusch VW, et al. Costeffectiveness of pulmonary resection and systemic chemotherapy in the management of metastatic soft tissue sarcoma: A combined analysis from the University of Texas M. D. Anderson and Memorial Sloan-Kettering Cancer Centers. J Thorac Cardiovasc Surg 2004;127: Temeck BK, Wexler LH, Steinberg SM, McClure LL, Horowitz M, Pass HI. Metastasectomy for sarcomatous pediatric histologies: results and prognostic factors. Ann Thorac Surg 1995;59: Beattie EJ, Harvey JC, Marcove R, Martini N. Results of multiple pulmonary resections for metastatic osteogenic sarcoma after two decades. J Surg Oncol 1991;46: Briccoli A, Rocca M, Salone M, et al. Resection of recurrent pulmonary metastases in patients with osteosarcoma. Cancer 2005;104: Murthy SC, Kim K, Rice TW, et al. Can we predict long-term survival after pulmonary metastasectomy for renal cell carcinoma? Ann Thorac Surg 2005;79: Pfannschmidt J, Hoffmann H, Muley T, et al. Prognostic factors for survival after pulmonary resection of metastatic renal cell carcinoma. Ann Thorac Surg 2002;74: Assouad J, Petkova B, Berna P, Dujon A, Foucault C, Riquet M. Renal cell carcinoma lung metastases surgery: pathologic findings and prognostic factors. Ann Thorac Surg 2007;84: Petersen R, Hanish S, Haney J, et al. Improved survival with pulmonary metastasectomy: an analysis of 1720 patients with pulmonary metastatic melanoma. J Thorac Cardiovasc Surg 2007;133: Friedel G, Pastorino U, Ginsberg RJ, et al. Results of lung metastasectomy from breast cancer: prognostic criteria on the basis of 467 cases of the International Registry of lung metastases. Eur J Cardiothorac Surg 2002;22: Yamamoto K, Yoshikawa H, Shiromizu K, et al. Pulmonary metastasectomy for uterine cervical cancer: a multivariate analysis. Ann Thorac Surg 2004;77: Smith CP, Sharma A, Ayala G, Cagle P, Kadmon D. Solitary pulmonary metastasis from prostate cancer. J Urol 1999;162: McCormack PE, Bains MS, Begg CB, et al. Role of videoassisted thoracic surgery in the treatment of pulmonary metastases: results of a prospective trial. Ann Thorac Surg 1996;62: Parsons AM, Ennis EK, Yankaskas BC, et al. Helical computed tomography inaccuracy in the detection of pulmonary metastases: can it be improved? Ann Thorac Surg 2007;84: Kang MC, Kang CH, Lee HJ, et al. Accuracy of 16-channel multi-detector row chest computed tomography with thin sections in the detection of metastatic pulmonary nodules. Eur J Cardiothorac Surg 2008;33: Fortes DL, Allen MS, Lowe VJ, et al. The sensitivity of 18F-fluorodeoxyglucose positron emission tomography in the evaluation of metastatic pulmonary nodules. Eur J Cardiothorac Surg 2008;34:

9 2060 REVIEW ERHUNMWUNSEE AND D AMICO Ann Thorac Surg PULMONARY METASTASES 2009;88: Roth JA, Pass HI, Wesley MN, et al. Comparison of median sternotomy and thoracotomy for resection of pulmonary metastases in patients with adult soft-tissue sarcomas. Ann Thorac Surg 1986;42: Petersen RP, Pham D, Burfeind WR, et al. Thoracoscopic lobectomy facilitates the delivery of chemotherapy after resection for lung cancer. Ann Thorac Surg 2007;83: Onaitis MW, Petersen RP, Balderson SS, et al. Thoracoscopic lobectomy is a safe and versatile procedure: experience with 500 consecutive patients. Ann Surg 2006;244: Ninomiya M, Nakajima J, Tanaka M, et al. Effects of lung metastasectomy on respiratory function. Jpn J Thorac Cardiovasc Surg 2001;49: Liu HP, Lin PJ, Hsieh MJ, et al. Application of thoracoscopy for lung metastases. Chest 1995;107: Dowling RD, Landreneau RJ, Miller DL. Video-assisted thoracoscopic surgery for resection of lung metastases. Chest 1998;113: Dowling RD, Keenan RJ, Ferson PF, et al. Video assisted thoracoscopic surgery of pulmonary metastases. Ann Thorac Surg 1993;56: Cerfolio RJ, Bryant AS. Is palpation of the nonresected pulmonary lobe(s) required for patients with non small cell lung cancer? A prospective study. J Thorac Cardiovasc Surg 2008;135: Sonett JR. Pulmonary metastases: biologic and historical justification for VATS Eur J Cardiothorac Surg 1999;16(Suppl 1): S Gossot D, Radu C, Girard P, Le Cesne A, Bonvalot S. Resection of pulmonary metastases from sarcoma: can some patients benefit from a less invasive approach? Ann Thorac Surg 2009;87: Nakajima J, Murakawa T, Fukami T, et al. Is thoracoscopic surgery justified to treat pulmonary metastasis from colorectal cancer? Interact Cardiovasc Thorac Surg 2008;7: Mutsaerts EL, Zoetmulder FA, Meijer S, et al. Long term survival of thoracoscopic metastasectomy vs metastasectomy by thoracotomy in patients with a solitary pulmonary lesion. Eur J Surg Oncol 2002;28: Detterbeck FC, Egan TM. Thoracoscopy using a substernal handport for palpation. Ann Thorac Surg 2004;78: Mineo TC, Ambrogi V, Mineo D. Pompeo E. Transxiphoid hand-assisted video thoracoscopic surgery. Ann Thorac Surg 2007;83: Kandioler D, Kromer E, Tuchler H, et al. Long-term results after repeated surgical removal of pulmonary metastases. Ann Thorac Surg 1998;65: van Putte BP, Hendriks JM, Romjin S, et al. Combination chemotherapy with gemcitabine with isolated lung perfusion for the treatment of pulmonary metastases. J Thorac Cardiovasc Surg 2005;130: Hendricks JM, Grootenboers JH, Schramel FM, et al. Isolated lung perfusion with melphalan for resectable lung metastases: a phase I clinical trial. Ann Thorac Surg 2004;78: Van Schil PE, Hendriks JM, van Putte BP, et al. Isolated lung perfusion and related techniques for the treatment of pulmonary metastases. Eur J Cardiothorac Surg 2008;33: Brown WT, Wu X, Fowler JF, et al. Lung metastases treated by Cyberknife image-guided robotic stereotactic radiosurgery at 41 months. South Med J 2008;101: King J, Glenn D, Clark W, et al. Percutaneous radiofrequency ablation of pulmonary metastases in patients with colorectal cancer. Br J Surg 2004;91: