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Clinical trials for pulmonary metastasectomy
Clinical Trials for Pulmonary Metastasectomy Amit N. Patel, Jason Lamb, Nilesh Patel, Ricardo S. Santos, Christos Stavropoulos, and Rodney J. Landreneau There remains great controversy as to the indications and true benefits for pulmonary metastasectomy. The number of metastatic lesions, length of disease-free interval, and unilaterality has shown to be important prognostic factors on overall survival. In this review, we evaluate a number of clinical trials and critically assess the rational to perform pulmonary metastasectomy, which is a local treatment for a systemic disease process. © 2003 Elsevier Inc. All rights reserved. Key words: Metastasectomy, lung resection.
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esection of pulmonary metasteses was first performed in the late 1800s by Weinlechner for metstatic rib sarcoma, where successful resection of the lung and the associated chest wall was performed. In a series by Alexander and Haight, 10 (42%) of the patients had pneumonectomy and 12 (50%) had at least a lobectomy. They reported this early experience from the University of Michigan where they had a 5-year survival of 20% performing pulmonary metastatectomies. Their operative technique involved performing a pneumonectomy in all patients with metastatic lesions, with no mortality and a median survival of 7.5 months. Churchill reported long-term survival after resection of pulmonary metastasis from renal cell carcinoma in the last 1930s. The experience at the memorial hospital in New York, during the 1960s, demonstrated improved survival in patients with metastatic osteosarcoma to the lung, even involving multiple lesions. The International Registry of Lung Metastases was established in 1991 to assess the long-term results of pulmonary metastasectomy. The Registry has accrued 5206 cases of lung metastasectomy. They noted that if complete resection was performed, the 5-year survival was 33% for patients with a disease-free interval of 0-11 months and 45% for those with a disease-free interval of more
From the Section of Thoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA. Address reprint requests to Rodney J. Landreneau, MD, Section of Thoracic Surgery, University of Pittsburgh Medical Center, Suite C-800, Pittsburgh, PA 15213. © 2003 Elsevier Inc. All rights reserved. 1043-0679/03/1504-0017$30.00/0 doi:10.1053/j.semtcvs.2003.10.001
than 36 months; 43% for single lesions and 27% for four or more lesions. Survival after complete metastasectomy was 36% at 5 years, 26% at 10 years, and 22% at 15 years (median 35 months). When evaluating patients for metastatectomy, Aberg noted the following factors that must be considered. The primary tumor has to have been removed and no other organ metastases are found (this weeds out patients with spread disease). Locally, the disease is eradicated (this weeds out patients with local recurrence). Some kind of interval between the primary organ operation and the metastasectomy is often advocated (this gives the tumor the chance of showing its real nature). The patient is suitable for operation by ordinary criteria (this weeds out patients with poor prognosis from other diseases). Using these criteria, he stated that patients could truly be identified who may benefit from surgical intervention. There have been many advances in the surgical, radiological, and molecular techniques used to manage metastatic lesions to the lung. We discuss the possible management scenarios for these patients.
Introduction The greatest concern regarding treatment of metastatic lesions to the lung is that how can a regional therapy (pulmonary metastasectomy) be successful in the management of a systemic malignant process. The fact is that patients who may be candidates for therapeutic pulmonary metastasectomy represent a very small fraction of those patients with a recurrent malignancy. Patients with pulmonary metastases from colorectal carcinoma offer a good example of this. Over
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130,000 patients are diagnosed with colorectal carcinoma each year in the United States. Over 50% of these patients will develop recurrent disease. Only 10% of these patients will develop clinically isolated metastases to the lungs. Ten percent of this latter group of patients with limited metastatic burden to the lung (1% of total recurrences) may be candidates for therapeutic metastasectomy. Between 25 and 40% of these colorectal cancer patients undergoing pulmonary metastasectomy may survive 5 years following surgery; however, the majority of these patients will succumb to colorectal cancer before the 10year mark.1-6 To make interpretation of these results of pulmonary metastasectomy more complicated, it is appreciated that a small number of patients with pulmonary metastases who receive no resection may survive beyond 5 years from diagnosis of their metastatic disease.4,6-12 The clinical scenario exemplified among patients with colorectal pulmonary metastases is similar to that seen among other recurrent malignant histologies approached with pulmonary metastasectomy.1-3,13-18 This leads us to question the true clinical value of therapeutic metastasectomy for the vast majority of patients with this pulmonary manifestation of their disease. The contribution to patient survival related to the indolent nature of the malignant metastatic process among long-term survivors of pulmonary metastasectomy must also be considered. This is particularly the case among pulmonary metastasectomy patients with recurrent pulmonary disease who remain alive for extended periods of time following their surgical resection. Aberg has clearly described the basic patient selection criteria for therapeutic metastasectomy utilized by many of us today. In brief, these criteria are: local control of the primary malignancy, a long disease-free interval from primary tumor resection, no effective alternative therapy, absence of extrathoracic metastases, and the presence of a limited pulmonary metastatic burden that can be completely resected. Although these guidelines are recognized as generally valid, many thoracic surgeons writing about pulmonary metastasectomy admit that their patient selection is not absolutely governed by the results of data analyses.2,5,9,13,15,19,20 This tendency to consider metastasectomy more liberally is the result of our general obsession as physicians to do something for our patient with a
disease process that has no other effective systemic treatment. It probably also stems from the primordial belief that we can help these patients by removing the obvious component of the patient’s systemic disease (ie, lung nodules). These beliefs are fostered early in our medical education. It may be more noble for our patient to succumb with surgery than to simply linger til death on the medicine ward. These biases are also shared by many of our patients, who remain disinclined toward systemic therapy options that are noted for their prolonged course and the fear of unsavory side effects that frequently distort one’s self image (ie, weight change, nausea/vomiting, malaise, and hair loss). As controlled studies comparing metastasectomy to best medical care are lacking, we must extrapolate our management concepts from the often serendipitous and routinely archival reports of metastasectomy, which are at hand in the literature. Despite the metastasectomy dogma professed by some, we contend that metastasectomy has a very limited therapeutic role in the management of cancer patients with pulmonary metastases. We even more firmly believe that radical pulmonary metastasectomy has even less of a therapeutic role and that this latter approach may actually cause more physiologic harm than oncologic treatment good. We will address a few controversial issues regarding the selection for and the conduct of therapeutic metastasectomy that speak against radical resection approaches.
Complete Resection of All Metastatic Disease It is commonly stated that long-term survival following pulmonary metastasectomy is only observed among those patients who have had complete removal of all metastatic deposits within the lung.2,6,13,15,19,21-24 This is in itself a misleading concept, which suggests that a scrupulous search for every minute pulmonary metastases has been the rule for each patient undergoing pulmonary metastasectomy. It also suggests that neglecting the resection of every abnormal site in the lung that could possibly be a metastasis, for fear of missing a metastatic deposit, dooms the patient to certain death from their systemic malignant disease.
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Although this broad concept has some intuitive appeal, we are left with many uncertainties from this message. If this meticulous attempt to locate any lung lesion is of such paramount importance, how is it that the majority of patients undergoing metastasectomy in any clinical series have had only one or two metastatic foci removed from their lungs at the time of metastasectomy. This is particularly perplexing when we reflect on the fact that most patients undergoing metastasectomy will develop subsequent recurrent pulmonary disease.1,2,25-27 Obviously, the presence of occult metastatic disease is the real problem here and not the lack of preoperative/intraoperative investigation and resection of clinically apparent metastases by the diligent thoracic surgeon. It is also interesting to note that nearly all patients who benefit from metastasectomy have only one or two lesions that were amenable to wedge resection.5,7,8,12,21,27-31 The selected survival advantage that is seen in these patients primarily results from the indolent biology of the tumor rather than to some special benefit from radical resection approaches to their metastatic disease. In establishing their argument for complete resection, some authors use a subset of patients with unresectable disease and/or with significant impairment in cardiopulmonary reserve as a control group to reference the poor prognosis seen among patients who have not undergone resectional therapy of their pulmonary metastases. Indeed, in one series patients who did not undergo resection at the time of thoracotomy had brachytherapy applied, which suggests that the metastatic disease was bulky and strategically impossible to resect without undo risk to these patients.23 It is obviously inappropriate to compare the survival seen in these unresectable patients with that of the much larger contingency of good functional class patients who are selected to undergo pulmonary resection. It is also confusing to believe the argument that careful bimanual inspection of the lung parenchyma is the only way of determining complete eradication of all lesions during the course of the metastasectomy procedure. Actually, this philosophy has only been shown to increase the finding of additional pulmonary lesions (benign and malignant) without providing any objective improvement in long-term survival.32,33 Additionally, it is paradoxical that many of the authors arguing for this open manual pulmonary exami-
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nation describe the use of a unilateral thoracotomy to approach the metastatic process. Most of these investigators are aware that Roth and coworkers have reported the finding of contralateral disease in a significant minority of patients preoperatively presumed to have only unilateral disease.34 Interestingly, Roth could not find any difference in survival among those patients undergoing bilateral simultaneous (transsternal) metastasectomy and metastasectomy performed only through a unilateral thoracotomy.34 Present day thin-cut spiral computed tomography (CT) scanning techniques present us with an intriguing new problem of overcalling possible malignancy in minute lesions that were heretofore not appreciated with standard chest roentgenography and CT techniques or with manual palpation.35 On the positive side, these CT scans can identify circumstances where diffuse metastatic involvement precludes the role for any therapeutic lung resection. However, the findings of additional lesions from these studies can also lead surgeons with a surgical philosophy toward radical therapeutic metastasectomy to attempt resection of innocent peripheral lung lesions, which may lead to unnecessary loss of normal pulmonary parenchyma. Another point of contention regarding this concept of complete resection involves the advocacy of multiple recurrent thoracotomies to clear the patient of recurrent metastatic pulmonary nodules.7,15,21,25,26,32,36-39 Examination of the amount of resection in these reports impresses us with the courage of these patients and their loyalty to their surgeons. However, these clinical scenarios cannot objectively support the argument that repeated surgical resection affected survival in a positive way. Indeed, it can be argued that the long-term survivors’ quality of life may actually have been significantly disaffected by the repeated attempts at eradication of their obviously indolent tumors.
Overall Survival Versus Tumor-Free Survival Clarification of the differences between post-metastasectomy overall survival and post-metastasectomy tumor-free survival is of obvious importance in determining the therapeutic role of pulmonary metastasectomy. This information is vital in determining whether survival was primar-
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ily affected by an indolent tumor biology of the metastastic tumor or to tumor eradication through surgery. Unfortunately, this distinction is usually presented vaguely (or not at all) in many of the reports at hand in the literature. Interestingly, the role of metastasectomy even in the most favorable group of patients with solitary metastases has been questioned, as longterm survival has been witnessed among patients whose solitary metastatic nodule was elected to be observed rather than resected.10,11
Role of Tumor Markers in Prognosticating Survival Following Metastasectomy A number of studies have alluded to the importance of serum levels of tumor markers and tissue hormonal concentration in determining the potential resectional benefit of presumed pulmonary metastases from a variety of histologic primary tumors. Serial determination of serum tumor markers can also assist in determining the potential response to therapy and in identifying patients with probable recurrent malignant disease following resection. These serum levels should become a routine part of the preoperative evaluation of patients with metastases from certain tumor histologies rather than primarily relying on the technical resectability of the metastatic foci.4,9,12,13,40
Contribution of Systemic Therapy in the Management of Pulmonary Metastases Improvements in the systemic therapy of many malignancies has markedly changed the natural history of malignant diseases for which pulmonary metastasectomy was previously believed to be the only hope for patient salvage. This is particularly evident among patient with soft tissue sarcoma. Depending on the origin of the sarcoma, time to occurrence and the number of pulmonary metastases developing has been significantly altered with the use of adjuvant systemic therapy following primary tumor resection compared with that of historical controls.41-43 It is difficult to determine pulmonary metastasectomy’s relative contribution to overall patient survival when such adjuvant systemic chemotherapy has also been utilized. It is certainly illegitimate to compare the results of this surgical/systemic therapy management (which may include pulmo-
nary metastasectomy) against historical control patients who only underwent resection of their primary site of sarcoma. It is of further importance to recognize that it is inappropriate to include tumor histologies that are highly curable through systemic therapy into clinical series supporting the role of pulmonary metastasectomy. Germ cell tumors are a good example of this circumstance. The primary role of pulmonary metastasectomy at this time in the management of these malignancies involves the determination of residual tumor for which further systemic therapy may be indicated. The majority of patients with these malignancies undergoing primary chemotherapy treatment will only have scar identified in posttreatment residual pulmonary nodules. The inclusion of such histologies into therapeutic metastasectomy series in the literature merely pads the metastasectomy results rather than truly supporting an important role for therapeutic pulmonary metastasectomy.44
Surgical Approach to Metastasectomy Lateral thoracotomy has been the approach most commonly described in the literature to accomplish pulmonary metastasectomy. This approach offers reasonable access to all areas of the hemithorax if a large enough intercostal incision is utilized. Alternatively, a smaller thoracotomy directed to the location of the lesion(s) in question can be utilized; however, this compromises exposure to other areas of the hemithorax. Wedge resection and anatomic resection can be readily accomplished under direct vision through the lateral thoracotomy approach, insuring adequate surgical margins and avoidance of chest wall contamination, which can be a concern when the video-assisted thoracoscopic surgical (VATS) approache is utilized.31,45-49 The major drawbacks of these approaches relate to the painful nature of the incision and inaccessibility to the contralateral hemithorax. Those championing a sternotomy approach to metastasectomy favor the ability to examine both lungs simultaneously and to simultaneously resect metastatic disease from both lungs.33,35,37,50 They also describe the frequent identification of occult disease that may have gone unrecognized when a lateral thoracotomy is utilized. Despite these arguments for vertical sternotomy, there
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does not appear to be a survival advantage for patients undergoing sternotomy for metastasectomy compared with a lateral thoracotomy approach. Additionally, exposure and resection of lesions in the posterior costovertebral aspects of the chest are difficult to accomplish through a vertical sternotomy approach. The use of a costotransverse sternotomy with bilateral thoracotomy (clamshell approach) can obviate these exposure problems51; however, postoperative discomfort is often increased compared with standard vertical sternotomy. We along with others have been interested in the use of VATS as an approach alternative to lateral thoracotomy and sternotomy approaches in an effort to reduce perioperative pain-related morbidity following pulmonary metastasectomy. VATS approaches are often applicable for both diagnostic and potentially therapeutic metastasectomy as many pulmonary metastases are located in the peripheral one-third of the lung. However, conversion to an open surgical approach is appropriate if deeper lesions are known to be present or if they are identified intraoperatively. Similarly, it is appropriate to convert to an open approach if it is not possible to identify all suspicious lesions in a timely fashion using VATS. Proper use of this technique for therapeutic metastasectomy is highly dependent on lesional size and location. Proper technical conduct of the VATS approach is also vital to avoid compromise of oncologic surgical principles. In general, the lesion(s) must be small and located in the outer third of the lung parenchyma. Endobronchial extension of the lesion should also be absent.31 Extraction of the specimen should be accomplished with a sterile specimen retrieval system to avoid intercostal access tract seeding with malignant cells. The bottom line regarding any of these operative approaches is that a survival advantage can only be offered if a limited number of metastatic nodules are present at metastasectomy.31,52,53 When more than a few (1-4) lesions are appreciated roentgenographically or at surgical exploration, the metastasectomy takes on a primarily diagnostic role. If a small number of lesions are identified and resected, a therapeutic role of metastasectomy may be appreciated in a select few patients. Any of the three surgical approaches (lateral thoracotomy, sternotomy, VATS) are valid technical options when skilled surgeons at-
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tempt resection of small target lesions located in the periphery of the lung. This is particularly the case when wedge excision is the resective approach utilized. For deeper-seated lesions requiring formal anatomic resection, an open surgical approach is usually necessary.
Conclusions The notion that removal of an obvious offending lesion is generally good for the patient is not a new concept. These beliefs are often held despite the known fact that lung metastases are by definition part of a systemic disease process. Shakespeare’s Macbeth was even known to plea “out damned spot.” However, his disturbance and preoccupation with those bloody spots did little to help the true troubles within himself. We surgeons and our patients alike are similarly plagued with the idea that all things could be well if we could only get rid of those troublesome lung “spots.” This quick-fix surgical approach is certainly more attractive (and noble) to many patients who fear the side effects (nausea/vomiting, hair loss, and malaise) of systemic therapy, which is usually presented to them as being palliative treatment only. Despite the volume of reports supporting pulmonary metastasectomy in the literature, the information at hand cannot distinguish between the relative contribution of this surgery, the possible effects of favorable tumor biology, and/or the improved effects of systemic therapy seen among these patients. As stated in the closing remarks of many of the reports of metastasectomy in the literature, determination of the role of metastasectomy for the majority of patients with metastases (presumed to be limited to the lungs) can only be determined through future prospective trials.2,7,12,16,18,31,54-56 At the present time, we believe in conservative use of pulmonary metastasectomy. We do not believe this message is far from the beliefs of most other thoracic surgeons, pulmonologists, and medical oncologists today. Metastasectomy may have a role in the management of the patient with a limited metastatic burden (1-4 nodules) identified after local control of the primary lesion has been assured and freedom from other sites of disease is determined. Development of a staging system for metastatic disease processes being considered for pulmonary metastasectomy
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is also needed.15 Appropriate tumor markers should be utilized to estimate occult tumor burden that may preclude any success with surgical resection. Under these circumstances, long-term disease-free survival may be anticipated in a small minority of patients with favorable tumor histologies. Outside of a strict protocol setting, we must carefully individualize the use of conservative metastasectomy only to those carefully selected patients with favorable prognostic factors for resection. It is otherwise inappropriate to continue chasing the tail of the systemic malignant disease that is present in the vast majority of patients with the use of radical pulmonary metastasectomy.
References 1. Miller FR: Biology of metastasis, in Roth JA, Ruckdeschel JC, Weisenburger TH (eds): Thoracic Oncology. Philadelphia, W.B. Saunders Co., 1989, pp 609-618 2. Roth JA: Resection of pulmonary metastases, in Roth JA, Ruckdeschel JC, Weisenburger TH (eds): Thoracic Oncology. Philadelphia, W.B. Saunders Co., 1989, pp 619-630 3. Kern KA, Pass HI, Roth JA: Surgical treatment of pulmonary metastases, in Rosenberg SA (ed): Surgical Treatment of Metastatic Cancer. Philadelphia, J.B. Lippincott Co., 1987, pp 69-100 4. Girard P, Ducreux M, Baldeyrou P, et al: Surgery for lung metastases from colorectal cancer: Analysis of prognostic factors. J Clin Oncol 14:2047-2053, 1996 5. Shirouzu K, Isomoto H, Hayashi A, et al: Surgical treatment for patients with pulmonary metastases after resection of primary colorectal carcinoma. Cancer 76:393-398, 1995 6. Rusch VW: Pulmonary metastasectomy. Current indications. Chest 107:322S-331S, 1995 7. Matthay RA, Arroliga AC: Resection of pulmonary metastases. Am Rev Respir Dis 148:1691-1696, 1993 8. Girard P, Ducreux M, Baldeyrou P, et al: Surgery for lung metastases from colorectal cancer: Analysis of prognostic factors. J Clin Oncol 14:2047-2053, 1996 9. McAfee MK, Allen MS, Trastek VF, et al: Colorectal lung metastases: Results of surgical excision. Ann Thoracic Surg 53:780-786, 1992 10. Aberg T, Malmberg KA, Nilsson B, et al: The effect of metastasectomy: Fact or fiction? Ann Thoracic Surg 30: 378-384, 1980 11. Casciato DA, Nagurka C, Tabbarah HJ: Prolonged survival with unresected pulmonary metastases. Ann Thoracic Surg 36:202-208, 1993 12. Okumura S, Kondo H, Tsuboi M, et al: Pulmonary resection for metastatic colorectal cancer: Experiences with 159 patients. J Thoracic Cardiovasc Surg 112:867-874, 1996 13. Lanza LA, Natarajan G, Roth JA, et al: Long-term survival after resection of pulmonary metastases from carcinoma of the breast. Ann Thoracic Surg 54:244-248, 1992
14. Girard P, Baldeyrou P, LeChevalier T, et al: Surgery for pulmonary metastases: Who are the 10-year survivors? Cancer 74:2791-2797, 1994 15. Pastorino U, Buyse M, Friedel G, et al. Long-term results of lung metastasectomy: Prognostic analyses based on 5,206 cases. The International Registry of Lung Metastases. J Thoracic Cardiovasc Surg 113:37-49, 1997 16. Underwood MJ, Graham TR, Bailey JS: The role of surgery in the management of pulmonary metastasis. J Royal Soc Med 85:719-720, 1992 17. Moores DWO: Pulmonary metastases revisited. Ann Thoracic Surg 52:178, 1991 18. Joseph WL, Morton DL, Adkins PC: Prognostic significance of tumor doubling time in evaluating operability in pulmonary metastatic disease. J Thoracic Cardiovasc Surg 23:23-31, 1971 19. Roth JA, Putnam JB, Wesley MN, et al: Differing determinants of prognosis following resection of pulmonary metastases from osteogenic and soft tissue sarcoma patients. Cancer 55:1361-1366, 1985 20. Gundry SR, Coran AG, Lemmer J, et al: The influence of tumor microfoci on recurrence and survival following pulmonary resection of metastatic osteogenic sarcoma. Ann Thoracic Surg 38:473-478, 1984 21. Putnam JB, Roth JA, Wesley MN, et al: Analysis of prognostic factors in patients undergoing resection of pulmonary metastases from soft tissue sarcomas. J Thoracic Cardiovasc Surg 87:260-268, 1984 22. Vogt-Moykopf I, Krysa S, Bulzebruck H, et al: Surgery for pulmonary metastases. The Heidelberg experience. Chest Surg Clin N Am 4:85-112, 1994 23. McCormack PM, Burt ME, Bains MS, et al: Lung resection for colorectal metastases. 10-year results. Arch Surg 127:1403-1406, 1992 24. Rusch VW: Pulmonary metastasectomy: Current indications. Chest 107:322S-332S, 1995 25. Girard P, Baldeyrou P, LeChevalier T, et al: Surgical resection of pulmonary metastases. Up to what number? Am J Respir Crit Care Med 149:469-476, 1994 26. Frost DB: Pulmonary metastasectomy for soft tissue sarcomas: Is it justified? J Surg Oncol 59:110-115, 1995 27. Shimizu J, Oda M, Hayashi Y, et al: Results of surgical treatment of pulmonary metastases. J Surg Oncol 58:5762, 1995 28. Cozzoli A, Milano S, Cancarini G, et al: Surgery of lung metastases in renal cell carcinoma. Br J Urol 75:445-447, 1995 29. van Halteren HK, van Geel AN, Hart AA, et al: Pulmonary resection for metastases of colorectal origin. Chest 107:1526-1531, 1995 30. Goya T, Miyazawa N, Kondo H, et al: Surgical resection of pulmonary metastases from colorectal cancer. 10-year follow-up. Cancer 64:1418-1421, 1989 31. Landreneau RJ, Mack MJ, Hazelrigg SR, et al: Videoassisted thoracic surgery: A minimally invasive approach to thoracic oncology, in DeVita VT, Hellman S, Rosenberg SA (eds.) : Cancer: Principles & Practice of Oncology Updates, vol. 8, Philadelphia, 1994, Lippincott, pp 1-14 32. Pogrebniak HW, Haas G, Linehan M, et al: Renal cell carcinoma: Resection of solitary and multiple metastases. Ann Thoracic Surg 54:33-38, 1992
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33. Pastorino U, Valente M, Gasparini M, et al: Median sternotomy and multiple lung resections for metastatic sarcomas. Eur J Cardiothoracic Surg 4:477-481, 1990 34. 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 Thoracic Surg 42:134-138, 1986 35. Remy-Jardin M, Remy J, Giraud F, et al: Pulmonary nodules: Detection with thin-section spiral CT versus conventional CT. Radiology 187:513-520, 1993 36. Rizzoni WE, Pass HI, Wesley MN, et al: Resection of recurrent pulmonary metastases in patients with softtissue sarcomas. Arch Surg 121:1248-1252, 1986 37. Beattie EJ, Harvey JC, Marcove R, et al: Results of multiple pulmonary resections for metastatic osteogenic sarcoma after two decades. J Surg Oncol 46:154-155, 1991 38. Pogrebniak HW, Pass HI: Initial and reoperative pulmonary metastasectomy. Indications, techniques and results. Semin Surg Oncol 9:142-149, 1993 39. Putnam JB, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematol Oncol Clin N Am 9:869-887, 1995 40. Quillien V, Ramee MP, Bansard JY, et al: Serum and tissue distribution of a fragment of cytokeratin 19 (cyfra 21-1) in lung cancer patients. Anticancer Res 15:28572863, 1995 41. Rosenberg SA, Tepper J, Glatstein E, et al: Prospective randomized evaluation of adjuvant chemotherapy in adults with soft tissue sarcomas of the extremities. Cancer 52:424-434, 1983 42. Eilber FR, Huth JF, Mirra J, et al: Progress in the recognition and treatment of soft tissue sarcomas. Cancer 65:660-666, 1990 43. Jaffe N, Smith E, Abelson HT, et al: Osteogenic sarcoma: Alterations in the pattern of pulmonary metastases with adjuvant chemotherapy. J Clin Oncol 1:251-254, 1983 44. Prenger K, Eysman L, Homan van der Heide JN, et al: Thoracotomy as a staging procedure after chemotherapy in the treatment of stage III nonseminomatous carcinoma of the testis. Ann Thoracic Surg 38:444-446, 1984
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45. McCormack PM, Bains MS, Begg CB, et al: Role of video-assisted thoracic surgery in the treatment of pulmonary metastases: Results of a prospective trial. Ann Thoracic Surg 62:213-216, 1996 46. Downey RJ, McCormack P, LoCicero J: Dissemination of malignant tumors after video-assisted thoracic surgery: A report of twenty-one cases. The Video-Assisted Thoracic Surgery Study Group. J Thoracic Cardiovasc Surg 111: 954-960, 1996 47. Fry WA, Siddiqui A, Pensler JM, et al: Thoracoscopic implantation of cancer with a fatal outcome. Ann Thoracic Surg 59:42-45, 1995 48. Walsh GL, Nesbitt JC: Tumor implants after thoracoscopic resection of a metastatic sarcoma. Ann Thoracic Surg 59:215-216, 1995 49. McCormack PM, Ginsberg KB, Bains MS, et al: Accuracy of lung imaging in metastases with implications for the role of thoracoscopy. Ann Thoracic Surg 56:863866, 1993 50. Johnston MR: Median sternotomy for resection of pulmonary metastases. J Thoracic Cardiovasc Surg 85:516-522, 1983 51. Bains MS, Ginsberg RJ, Jones WG, et al: The clamshell incision: An improved approach to bilateral pulmonary and mediastinal tumor. Ann Thoracic Surg 58:30-33, 1994 52. Dowling RD, Keenan RJ, Ferson PF, et al: Video-assisted thoracoscopic surgery for pulmonary metastases. Ann Thoracic Surg 56:772-775, 1993 53. Liu HP, Lin PJ, Hsieh MJ, et al: Application of thoracoscopy for lung metastases. Chest 107:266-268, 1995 54. Harpole DH, Johnson CM, Wolfe WG, et al: Analysis of 945 cases of pulmonary metastatic melanoma. J Thoracic Cardiovasc Surg 103:743-750, 1992 55. Wagner JS, Adson MA, Van Heerden JA, et al: The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Hepatic Metastases 199:502-508, 1984 56. Hammond GL: Should pulmonary metastases be resected? Chest 107:1485, 1995
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esection of pulmonary metasteses was first performed in the late 1800s by Weinlechner for metstatic rib sarcoma, where successful resection of the lung and the associated chest wall was performed. In a series by Alexander and Haight, 10 (42%) of the patients had pneumonectomy and 12 (50%) had at least a lobectomy. They reported this early experience from the University of Michigan where they had a 5-year survival of 20% performing pulmonary metastatectomies. Their operative technique involved performing a pneumonectomy in all patients with metastatic lesions, with no mortality and a median survival of 7.5 months. Churchill reported long-term survival after resection of pulmonary metastasis from renal cell carcinoma in the last 1930s. The experience at the memorial hospital in New York, during the 1960s, demonstrated improved survival in patients with metastatic osteosarcoma to the lung, even involving multiple lesions. The International Registry of Lung Metastases was established in 1991 to assess the long-term results of pulmonary metastasectomy. The Registry has accrued 5206 cases of lung metastasectomy. They noted that if complete resection was performed, the 5-year survival was 33% for patients with a disease-free interval of 0-11 months and 45% for those with a disease-free interval of more
From the Section of Thoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA. Address reprint requests to Rodney J. Landreneau, MD, Section of Thoracic Surgery, University of Pittsburgh Medical Center, Suite C-800, Pittsburgh, PA 15213. © 2003 Elsevier Inc. All rights reserved. 1043-0679/03/1504-0017$30.00/0 doi:10.1053/j.semtcvs.2003.10.001
than 36 months; 43% for single lesions and 27% for four or more lesions. Survival after complete metastasectomy was 36% at 5 years, 26% at 10 years, and 22% at 15 years (median 35 months). When evaluating patients for metastatectomy, Aberg noted the following factors that must be considered. The primary tumor has to have been removed and no other organ metastases are found (this weeds out patients with spread disease). Locally, the disease is eradicated (this weeds out patients with local recurrence). Some kind of interval between the primary organ operation and the metastasectomy is often advocated (this gives the tumor the chance of showing its real nature). The patient is suitable for operation by ordinary criteria (this weeds out patients with poor prognosis from other diseases). Using these criteria, he stated that patients could truly be identified who may benefit from surgical intervention. There have been many advances in the surgical, radiological, and molecular techniques used to manage metastatic lesions to the lung. We discuss the possible management scenarios for these patients.
Introduction The greatest concern regarding treatment of metastatic lesions to the lung is that how can a regional therapy (pulmonary metastasectomy) be successful in the management of a systemic malignant process. The fact is that patients who may be candidates for therapeutic pulmonary metastasectomy represent a very small fraction of those patients with a recurrent malignancy. Patients with pulmonary metastases from colorectal carcinoma offer a good example of this. Over
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130,000 patients are diagnosed with colorectal carcinoma each year in the United States. Over 50% of these patients will develop recurrent disease. Only 10% of these patients will develop clinically isolated metastases to the lungs. Ten percent of this latter group of patients with limited metastatic burden to the lung (1% of total recurrences) may be candidates for therapeutic metastasectomy. Between 25 and 40% of these colorectal cancer patients undergoing pulmonary metastasectomy may survive 5 years following surgery; however, the majority of these patients will succumb to colorectal cancer before the 10year mark.1-6 To make interpretation of these results of pulmonary metastasectomy more complicated, it is appreciated that a small number of patients with pulmonary metastases who receive no resection may survive beyond 5 years from diagnosis of their metastatic disease.4,6-12 The clinical scenario exemplified among patients with colorectal pulmonary metastases is similar to that seen among other recurrent malignant histologies approached with pulmonary metastasectomy.1-3,13-18 This leads us to question the true clinical value of therapeutic metastasectomy for the vast majority of patients with this pulmonary manifestation of their disease. The contribution to patient survival related to the indolent nature of the malignant metastatic process among long-term survivors of pulmonary metastasectomy must also be considered. This is particularly the case among pulmonary metastasectomy patients with recurrent pulmonary disease who remain alive for extended periods of time following their surgical resection. Aberg has clearly described the basic patient selection criteria for therapeutic metastasectomy utilized by many of us today. In brief, these criteria are: local control of the primary malignancy, a long disease-free interval from primary tumor resection, no effective alternative therapy, absence of extrathoracic metastases, and the presence of a limited pulmonary metastatic burden that can be completely resected. Although these guidelines are recognized as generally valid, many thoracic surgeons writing about pulmonary metastasectomy admit that their patient selection is not absolutely governed by the results of data analyses.2,5,9,13,15,19,20 This tendency to consider metastasectomy more liberally is the result of our general obsession as physicians to do something for our patient with a
disease process that has no other effective systemic treatment. It probably also stems from the primordial belief that we can help these patients by removing the obvious component of the patient’s systemic disease (ie, lung nodules). These beliefs are fostered early in our medical education. It may be more noble for our patient to succumb with surgery than to simply linger til death on the medicine ward. These biases are also shared by many of our patients, who remain disinclined toward systemic therapy options that are noted for their prolonged course and the fear of unsavory side effects that frequently distort one’s self image (ie, weight change, nausea/vomiting, malaise, and hair loss). As controlled studies comparing metastasectomy to best medical care are lacking, we must extrapolate our management concepts from the often serendipitous and routinely archival reports of metastasectomy, which are at hand in the literature. Despite the metastasectomy dogma professed by some, we contend that metastasectomy has a very limited therapeutic role in the management of cancer patients with pulmonary metastases. We even more firmly believe that radical pulmonary metastasectomy has even less of a therapeutic role and that this latter approach may actually cause more physiologic harm than oncologic treatment good. We will address a few controversial issues regarding the selection for and the conduct of therapeutic metastasectomy that speak against radical resection approaches.
Complete Resection of All Metastatic Disease It is commonly stated that long-term survival following pulmonary metastasectomy is only observed among those patients who have had complete removal of all metastatic deposits within the lung.2,6,13,15,19,21-24 This is in itself a misleading concept, which suggests that a scrupulous search for every minute pulmonary metastases has been the rule for each patient undergoing pulmonary metastasectomy. It also suggests that neglecting the resection of every abnormal site in the lung that could possibly be a metastasis, for fear of missing a metastatic deposit, dooms the patient to certain death from their systemic malignant disease.
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Although this broad concept has some intuitive appeal, we are left with many uncertainties from this message. If this meticulous attempt to locate any lung lesion is of such paramount importance, how is it that the majority of patients undergoing metastasectomy in any clinical series have had only one or two metastatic foci removed from their lungs at the time of metastasectomy. This is particularly perplexing when we reflect on the fact that most patients undergoing metastasectomy will develop subsequent recurrent pulmonary disease.1,2,25-27 Obviously, the presence of occult metastatic disease is the real problem here and not the lack of preoperative/intraoperative investigation and resection of clinically apparent metastases by the diligent thoracic surgeon. It is also interesting to note that nearly all patients who benefit from metastasectomy have only one or two lesions that were amenable to wedge resection.5,7,8,12,21,27-31 The selected survival advantage that is seen in these patients primarily results from the indolent biology of the tumor rather than to some special benefit from radical resection approaches to their metastatic disease. In establishing their argument for complete resection, some authors use a subset of patients with unresectable disease and/or with significant impairment in cardiopulmonary reserve as a control group to reference the poor prognosis seen among patients who have not undergone resectional therapy of their pulmonary metastases. Indeed, in one series patients who did not undergo resection at the time of thoracotomy had brachytherapy applied, which suggests that the metastatic disease was bulky and strategically impossible to resect without undo risk to these patients.23 It is obviously inappropriate to compare the survival seen in these unresectable patients with that of the much larger contingency of good functional class patients who are selected to undergo pulmonary resection. It is also confusing to believe the argument that careful bimanual inspection of the lung parenchyma is the only way of determining complete eradication of all lesions during the course of the metastasectomy procedure. Actually, this philosophy has only been shown to increase the finding of additional pulmonary lesions (benign and malignant) without providing any objective improvement in long-term survival.32,33 Additionally, it is paradoxical that many of the authors arguing for this open manual pulmonary exami-
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nation describe the use of a unilateral thoracotomy to approach the metastatic process. Most of these investigators are aware that Roth and coworkers have reported the finding of contralateral disease in a significant minority of patients preoperatively presumed to have only unilateral disease.34 Interestingly, Roth could not find any difference in survival among those patients undergoing bilateral simultaneous (transsternal) metastasectomy and metastasectomy performed only through a unilateral thoracotomy.34 Present day thin-cut spiral computed tomography (CT) scanning techniques present us with an intriguing new problem of overcalling possible malignancy in minute lesions that were heretofore not appreciated with standard chest roentgenography and CT techniques or with manual palpation.35 On the positive side, these CT scans can identify circumstances where diffuse metastatic involvement precludes the role for any therapeutic lung resection. However, the findings of additional lesions from these studies can also lead surgeons with a surgical philosophy toward radical therapeutic metastasectomy to attempt resection of innocent peripheral lung lesions, which may lead to unnecessary loss of normal pulmonary parenchyma. Another point of contention regarding this concept of complete resection involves the advocacy of multiple recurrent thoracotomies to clear the patient of recurrent metastatic pulmonary nodules.7,15,21,25,26,32,36-39 Examination of the amount of resection in these reports impresses us with the courage of these patients and their loyalty to their surgeons. However, these clinical scenarios cannot objectively support the argument that repeated surgical resection affected survival in a positive way. Indeed, it can be argued that the long-term survivors’ quality of life may actually have been significantly disaffected by the repeated attempts at eradication of their obviously indolent tumors.
Overall Survival Versus Tumor-Free Survival Clarification of the differences between post-metastasectomy overall survival and post-metastasectomy tumor-free survival is of obvious importance in determining the therapeutic role of pulmonary metastasectomy. This information is vital in determining whether survival was primar-
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ily affected by an indolent tumor biology of the metastastic tumor or to tumor eradication through surgery. Unfortunately, this distinction is usually presented vaguely (or not at all) in many of the reports at hand in the literature. Interestingly, the role of metastasectomy even in the most favorable group of patients with solitary metastases has been questioned, as longterm survival has been witnessed among patients whose solitary metastatic nodule was elected to be observed rather than resected.10,11
Role of Tumor Markers in Prognosticating Survival Following Metastasectomy A number of studies have alluded to the importance of serum levels of tumor markers and tissue hormonal concentration in determining the potential resectional benefit of presumed pulmonary metastases from a variety of histologic primary tumors. Serial determination of serum tumor markers can also assist in determining the potential response to therapy and in identifying patients with probable recurrent malignant disease following resection. These serum levels should become a routine part of the preoperative evaluation of patients with metastases from certain tumor histologies rather than primarily relying on the technical resectability of the metastatic foci.4,9,12,13,40
Contribution of Systemic Therapy in the Management of Pulmonary Metastases Improvements in the systemic therapy of many malignancies has markedly changed the natural history of malignant diseases for which pulmonary metastasectomy was previously believed to be the only hope for patient salvage. This is particularly evident among patient with soft tissue sarcoma. Depending on the origin of the sarcoma, time to occurrence and the number of pulmonary metastases developing has been significantly altered with the use of adjuvant systemic therapy following primary tumor resection compared with that of historical controls.41-43 It is difficult to determine pulmonary metastasectomy’s relative contribution to overall patient survival when such adjuvant systemic chemotherapy has also been utilized. It is certainly illegitimate to compare the results of this surgical/systemic therapy management (which may include pulmo-
nary metastasectomy) against historical control patients who only underwent resection of their primary site of sarcoma. It is of further importance to recognize that it is inappropriate to include tumor histologies that are highly curable through systemic therapy into clinical series supporting the role of pulmonary metastasectomy. Germ cell tumors are a good example of this circumstance. The primary role of pulmonary metastasectomy at this time in the management of these malignancies involves the determination of residual tumor for which further systemic therapy may be indicated. The majority of patients with these malignancies undergoing primary chemotherapy treatment will only have scar identified in posttreatment residual pulmonary nodules. The inclusion of such histologies into therapeutic metastasectomy series in the literature merely pads the metastasectomy results rather than truly supporting an important role for therapeutic pulmonary metastasectomy.44
Surgical Approach to Metastasectomy Lateral thoracotomy has been the approach most commonly described in the literature to accomplish pulmonary metastasectomy. This approach offers reasonable access to all areas of the hemithorax if a large enough intercostal incision is utilized. Alternatively, a smaller thoracotomy directed to the location of the lesion(s) in question can be utilized; however, this compromises exposure to other areas of the hemithorax. Wedge resection and anatomic resection can be readily accomplished under direct vision through the lateral thoracotomy approach, insuring adequate surgical margins and avoidance of chest wall contamination, which can be a concern when the video-assisted thoracoscopic surgical (VATS) approache is utilized.31,45-49 The major drawbacks of these approaches relate to the painful nature of the incision and inaccessibility to the contralateral hemithorax. Those championing a sternotomy approach to metastasectomy favor the ability to examine both lungs simultaneously and to simultaneously resect metastatic disease from both lungs.33,35,37,50 They also describe the frequent identification of occult disease that may have gone unrecognized when a lateral thoracotomy is utilized. Despite these arguments for vertical sternotomy, there
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does not appear to be a survival advantage for patients undergoing sternotomy for metastasectomy compared with a lateral thoracotomy approach. Additionally, exposure and resection of lesions in the posterior costovertebral aspects of the chest are difficult to accomplish through a vertical sternotomy approach. The use of a costotransverse sternotomy with bilateral thoracotomy (clamshell approach) can obviate these exposure problems51; however, postoperative discomfort is often increased compared with standard vertical sternotomy. We along with others have been interested in the use of VATS as an approach alternative to lateral thoracotomy and sternotomy approaches in an effort to reduce perioperative pain-related morbidity following pulmonary metastasectomy. VATS approaches are often applicable for both diagnostic and potentially therapeutic metastasectomy as many pulmonary metastases are located in the peripheral one-third of the lung. However, conversion to an open surgical approach is appropriate if deeper lesions are known to be present or if they are identified intraoperatively. Similarly, it is appropriate to convert to an open approach if it is not possible to identify all suspicious lesions in a timely fashion using VATS. Proper use of this technique for therapeutic metastasectomy is highly dependent on lesional size and location. Proper technical conduct of the VATS approach is also vital to avoid compromise of oncologic surgical principles. In general, the lesion(s) must be small and located in the outer third of the lung parenchyma. Endobronchial extension of the lesion should also be absent.31 Extraction of the specimen should be accomplished with a sterile specimen retrieval system to avoid intercostal access tract seeding with malignant cells. The bottom line regarding any of these operative approaches is that a survival advantage can only be offered if a limited number of metastatic nodules are present at metastasectomy.31,52,53 When more than a few (1-4) lesions are appreciated roentgenographically or at surgical exploration, the metastasectomy takes on a primarily diagnostic role. If a small number of lesions are identified and resected, a therapeutic role of metastasectomy may be appreciated in a select few patients. Any of the three surgical approaches (lateral thoracotomy, sternotomy, VATS) are valid technical options when skilled surgeons at-
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tempt resection of small target lesions located in the periphery of the lung. This is particularly the case when wedge excision is the resective approach utilized. For deeper-seated lesions requiring formal anatomic resection, an open surgical approach is usually necessary.
Conclusions The notion that removal of an obvious offending lesion is generally good for the patient is not a new concept. These beliefs are often held despite the known fact that lung metastases are by definition part of a systemic disease process. Shakespeare’s Macbeth was even known to plea “out damned spot.” However, his disturbance and preoccupation with those bloody spots did little to help the true troubles within himself. We surgeons and our patients alike are similarly plagued with the idea that all things could be well if we could only get rid of those troublesome lung “spots.” This quick-fix surgical approach is certainly more attractive (and noble) to many patients who fear the side effects (nausea/vomiting, hair loss, and malaise) of systemic therapy, which is usually presented to them as being palliative treatment only. Despite the volume of reports supporting pulmonary metastasectomy in the literature, the information at hand cannot distinguish between the relative contribution of this surgery, the possible effects of favorable tumor biology, and/or the improved effects of systemic therapy seen among these patients. As stated in the closing remarks of many of the reports of metastasectomy in the literature, determination of the role of metastasectomy for the majority of patients with metastases (presumed to be limited to the lungs) can only be determined through future prospective trials.2,7,12,16,18,31,54-56 At the present time, we believe in conservative use of pulmonary metastasectomy. We do not believe this message is far from the beliefs of most other thoracic surgeons, pulmonologists, and medical oncologists today. Metastasectomy may have a role in the management of the patient with a limited metastatic burden (1-4 nodules) identified after local control of the primary lesion has been assured and freedom from other sites of disease is determined. Development of a staging system for metastatic disease processes being considered for pulmonary metastasectomy
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is also needed.15 Appropriate tumor markers should be utilized to estimate occult tumor burden that may preclude any success with surgical resection. Under these circumstances, long-term disease-free survival may be anticipated in a small minority of patients with favorable tumor histologies. Outside of a strict protocol setting, we must carefully individualize the use of conservative metastasectomy only to those carefully selected patients with favorable prognostic factors for resection. It is otherwise inappropriate to continue chasing the tail of the systemic malignant disease that is present in the vast majority of patients with the use of radical pulmonary metastasectomy.
References 1. Miller FR: Biology of metastasis, in Roth JA, Ruckdeschel JC, Weisenburger TH (eds): Thoracic Oncology. Philadelphia, W.B. Saunders Co., 1989, pp 609-618 2. Roth JA: Resection of pulmonary metastases, in Roth JA, Ruckdeschel JC, Weisenburger TH (eds): Thoracic Oncology. Philadelphia, W.B. Saunders Co., 1989, pp 619-630 3. Kern KA, Pass HI, Roth JA: Surgical treatment of pulmonary metastases, in Rosenberg SA (ed): Surgical Treatment of Metastatic Cancer. Philadelphia, J.B. Lippincott Co., 1987, pp 69-100 4. Girard P, Ducreux M, Baldeyrou P, et al: Surgery for lung metastases from colorectal cancer: Analysis of prognostic factors. J Clin Oncol 14:2047-2053, 1996 5. Shirouzu K, Isomoto H, Hayashi A, et al: Surgical treatment for patients with pulmonary metastases after resection of primary colorectal carcinoma. Cancer 76:393-398, 1995 6. Rusch VW: Pulmonary metastasectomy. Current indications. Chest 107:322S-331S, 1995 7. Matthay RA, Arroliga AC: Resection of pulmonary metastases. Am Rev Respir Dis 148:1691-1696, 1993 8. Girard P, Ducreux M, Baldeyrou P, et al: Surgery for lung metastases from colorectal cancer: Analysis of prognostic factors. J Clin Oncol 14:2047-2053, 1996 9. McAfee MK, Allen MS, Trastek VF, et al: Colorectal lung metastases: Results of surgical excision. Ann Thoracic Surg 53:780-786, 1992 10. Aberg T, Malmberg KA, Nilsson B, et al: The effect of metastasectomy: Fact or fiction? Ann Thoracic Surg 30: 378-384, 1980 11. Casciato DA, Nagurka C, Tabbarah HJ: Prolonged survival with unresected pulmonary metastases. Ann Thoracic Surg 36:202-208, 1993 12. Okumura S, Kondo H, Tsuboi M, et al: Pulmonary resection for metastatic colorectal cancer: Experiences with 159 patients. J Thoracic Cardiovasc Surg 112:867-874, 1996 13. Lanza LA, Natarajan G, Roth JA, et al: Long-term survival after resection of pulmonary metastases from carcinoma of the breast. Ann Thoracic Surg 54:244-248, 1992
14. Girard P, Baldeyrou P, LeChevalier T, et al: Surgery for pulmonary metastases: Who are the 10-year survivors? Cancer 74:2791-2797, 1994 15. Pastorino U, Buyse M, Friedel G, et al. Long-term results of lung metastasectomy: Prognostic analyses based on 5,206 cases. The International Registry of Lung Metastases. J Thoracic Cardiovasc Surg 113:37-49, 1997 16. Underwood MJ, Graham TR, Bailey JS: The role of surgery in the management of pulmonary metastasis. J Royal Soc Med 85:719-720, 1992 17. Moores DWO: Pulmonary metastases revisited. Ann Thoracic Surg 52:178, 1991 18. Joseph WL, Morton DL, Adkins PC: Prognostic significance of tumor doubling time in evaluating operability in pulmonary metastatic disease. J Thoracic Cardiovasc Surg 23:23-31, 1971 19. Roth JA, Putnam JB, Wesley MN, et al: Differing determinants of prognosis following resection of pulmonary metastases from osteogenic and soft tissue sarcoma patients. Cancer 55:1361-1366, 1985 20. Gundry SR, Coran AG, Lemmer J, et al: The influence of tumor microfoci on recurrence and survival following pulmonary resection of metastatic osteogenic sarcoma. Ann Thoracic Surg 38:473-478, 1984 21. Putnam JB, Roth JA, Wesley MN, et al: Analysis of prognostic factors in patients undergoing resection of pulmonary metastases from soft tissue sarcomas. J Thoracic Cardiovasc Surg 87:260-268, 1984 22. Vogt-Moykopf I, Krysa S, Bulzebruck H, et al: Surgery for pulmonary metastases. The Heidelberg experience. Chest Surg Clin N Am 4:85-112, 1994 23. McCormack PM, Burt ME, Bains MS, et al: Lung resection for colorectal metastases. 10-year results. Arch Surg 127:1403-1406, 1992 24. Rusch VW: Pulmonary metastasectomy: Current indications. Chest 107:322S-332S, 1995 25. Girard P, Baldeyrou P, LeChevalier T, et al: Surgical resection of pulmonary metastases. Up to what number? Am J Respir Crit Care Med 149:469-476, 1994 26. Frost DB: Pulmonary metastasectomy for soft tissue sarcomas: Is it justified? J Surg Oncol 59:110-115, 1995 27. Shimizu J, Oda M, Hayashi Y, et al: Results of surgical treatment of pulmonary metastases. J Surg Oncol 58:5762, 1995 28. Cozzoli A, Milano S, Cancarini G, et al: Surgery of lung metastases in renal cell carcinoma. Br J Urol 75:445-447, 1995 29. van Halteren HK, van Geel AN, Hart AA, et al: Pulmonary resection for metastases of colorectal origin. Chest 107:1526-1531, 1995 30. Goya T, Miyazawa N, Kondo H, et al: Surgical resection of pulmonary metastases from colorectal cancer. 10-year follow-up. Cancer 64:1418-1421, 1989 31. Landreneau RJ, Mack MJ, Hazelrigg SR, et al: Videoassisted thoracic surgery: A minimally invasive approach to thoracic oncology, in DeVita VT, Hellman S, Rosenberg SA (eds.) : Cancer: Principles & Practice of Oncology Updates, vol. 8, Philadelphia, 1994, Lippincott, pp 1-14 32. Pogrebniak HW, Haas G, Linehan M, et al: Renal cell carcinoma: Resection of solitary and multiple metastases. Ann Thoracic Surg 54:33-38, 1992
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33. Pastorino U, Valente M, Gasparini M, et al: Median sternotomy and multiple lung resections for metastatic sarcomas. Eur J Cardiothoracic Surg 4:477-481, 1990 34. 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 Thoracic Surg 42:134-138, 1986 35. Remy-Jardin M, Remy J, Giraud F, et al: Pulmonary nodules: Detection with thin-section spiral CT versus conventional CT. Radiology 187:513-520, 1993 36. Rizzoni WE, Pass HI, Wesley MN, et al: Resection of recurrent pulmonary metastases in patients with softtissue sarcomas. Arch Surg 121:1248-1252, 1986 37. Beattie EJ, Harvey JC, Marcove R, et al: Results of multiple pulmonary resections for metastatic osteogenic sarcoma after two decades. J Surg Oncol 46:154-155, 1991 38. Pogrebniak HW, Pass HI: Initial and reoperative pulmonary metastasectomy. Indications, techniques and results. Semin Surg Oncol 9:142-149, 1993 39. Putnam JB, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematol Oncol Clin N Am 9:869-887, 1995 40. Quillien V, Ramee MP, Bansard JY, et al: Serum and tissue distribution of a fragment of cytokeratin 19 (cyfra 21-1) in lung cancer patients. Anticancer Res 15:28572863, 1995 41. Rosenberg SA, Tepper J, Glatstein E, et al: Prospective randomized evaluation of adjuvant chemotherapy in adults with soft tissue sarcomas of the extremities. Cancer 52:424-434, 1983 42. Eilber FR, Huth JF, Mirra J, et al: Progress in the recognition and treatment of soft tissue sarcomas. Cancer 65:660-666, 1990 43. Jaffe N, Smith E, Abelson HT, et al: Osteogenic sarcoma: Alterations in the pattern of pulmonary metastases with adjuvant chemotherapy. J Clin Oncol 1:251-254, 1983 44. Prenger K, Eysman L, Homan van der Heide JN, et al: Thoracotomy as a staging procedure after chemotherapy in the treatment of stage III nonseminomatous carcinoma of the testis. Ann Thoracic Surg 38:444-446, 1984
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45. McCormack PM, Bains MS, Begg CB, et al: Role of video-assisted thoracic surgery in the treatment of pulmonary metastases: Results of a prospective trial. Ann Thoracic Surg 62:213-216, 1996 46. Downey RJ, McCormack P, LoCicero J: Dissemination of malignant tumors after video-assisted thoracic surgery: A report of twenty-one cases. The Video-Assisted Thoracic Surgery Study Group. J Thoracic Cardiovasc Surg 111: 954-960, 1996 47. Fry WA, Siddiqui A, Pensler JM, et al: Thoracoscopic implantation of cancer with a fatal outcome. Ann Thoracic Surg 59:42-45, 1995 48. Walsh GL, Nesbitt JC: Tumor implants after thoracoscopic resection of a metastatic sarcoma. Ann Thoracic Surg 59:215-216, 1995 49. McCormack PM, Ginsberg KB, Bains MS, et al: Accuracy of lung imaging in metastases with implications for the role of thoracoscopy. Ann Thoracic Surg 56:863866, 1993 50. Johnston MR: Median sternotomy for resection of pulmonary metastases. J Thoracic Cardiovasc Surg 85:516-522, 1983 51. Bains MS, Ginsberg RJ, Jones WG, et al: The clamshell incision: An improved approach to bilateral pulmonary and mediastinal tumor. Ann Thoracic Surg 58:30-33, 1994 52. Dowling RD, Keenan RJ, Ferson PF, et al: Video-assisted thoracoscopic surgery for pulmonary metastases. Ann Thoracic Surg 56:772-775, 1993 53. Liu HP, Lin PJ, Hsieh MJ, et al: Application of thoracoscopy for lung metastases. Chest 107:266-268, 1995 54. Harpole DH, Johnson CM, Wolfe WG, et al: Analysis of 945 cases of pulmonary metastatic melanoma. J Thoracic Cardiovasc Surg 103:743-750, 1992 55. Wagner JS, Adson MA, Van Heerden JA, et al: The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Hepatic Metastases 199:502-508, 1984 56. Hammond GL: Should pulmonary metastases be resected? Chest 107:1485, 1995