Sarcomas may arise from nearly any embryonic mesodermal tissue and constitute approximately 1% of all newly diagnosed malignancies annually. Through hematogenous dissemination, rates of metastatic disease to the lungs have been reported to be as high as 20% for osteogenic sarcoma and 40% for soft-tissue sarcoma, and pulmonary metastases are present in most patients who die from sarcomatous malignancies. Furthermore, the pulmonary bed often is the only site of distant disease.[1-3] Sarcomas are the second most common cause of pulmonary metastatic disease, following colorectal cancer. The youthful demographic most often affected by sarcoma warrants an aggressive approach to metastases.
The Pathophysiology of Pulmonary Metastases
Tumor progression from the primary site to clinically detectable pulmonary metastases involves multiple complex steps, including vascular invasion, survival without an extracellular matrix (anoikis), immune system evasion, extravasation into the target organ, dormancy followed by proliferation, and angiogenesis. This pathway applies to all solid tumors, yet certain solid tumors preferentially metastasize to specific organs. Attempts to characterize this phenomenon date back to Paget in the late 19th century, with his proposal of a “seed” and “soil” theory. Paget theorized that certain elements within the tumor cell (seed) have an affinity for elements in the target organ (soil). This was challenged by Ewing in the early 20th century, who maintained that target organ anatomic variables were more critical. Ewing postulated that the frequency of lung metastases was related to the vast capillary system that could snare tumor cells, and the high oxygen tension that could support their growth. Although both theories are likely relevant to the lung as a primary site of metastases, more recent data evaluating pulmonary and tumor chemokine production and receptors have suggested that the “seed” and “soil” theory may have a more significant impact on the development of pulmonary metastases. Specifically, a primary chemokine produced by the lungs is CXCL12, and its cognate receptor is CXCR4. In both breast cancer and melanoma, the overexpression of the receptor CXCR4 has been associated with a dramatic increase in the rate of pulmonary metastases.[5,6] CXCR4 overexpression has also been demonstrated in soft-tissue sarcoma and seems to correlate with the targeting of metastases to lung and bone. Blocking this chemokine-receptor interaction represents a potentially clinically useful intervention for preventing metastases, but it likely would have little to no impact on existing lung lesions.
Therapeutic Interventions for Thoracic Metastases From Sarcoma
Traditionally, metastatic solid tumor treatment consists of systemic chemotherapy. In soft-tissue sarcoma, anthracycline-based regimens are considered standard of care, yet there has never been a prospective randomized controlled trial comparing this to best supportive care. Pulmonary resection of secondary lung tumors was first performed over 125 years ago. Numerous retrospective studies have shown better than expected outcomes with surgical resection when compared to no treatment or chemotherapy only, but these studies are subject to substantial selection bias. To date, there have been no randomized controlled trials evaluating the effect of pulmonary metastasectomy on survival. The most convincing evidence of the benefit of this approach came from an analysis of the International Registry of Lung Metastases. Pastorino and colleagues retrospectively reviewed 5,206 cases of pulmonary metastasectomy accrued to the registry from 1991 to 1995 from 9 different countries for a variety of cancers. Of the cases in this series, 42% were soft-tissue sarcoma. A stepwise decrease in 5-year survival was seen with the number of metastases: 43% with a single metastasis, 34% with two or three metastases, and 27% with four or more metastases. Additionally, the disease-free interval between resection of the primary tumor and detection of pulmonary metastasis was directly correlated with survival. Resectability, however, was the most important determinant of survival: overall median survival was 35 months in patients who had undergone complete resection and only 15 months in those patients who had an incomplete resection (Figures 1 and 2). These data can be compared to historical outcomes of best supportive care, with a median survival of 8 to 13 months,[9,10] and of chemotherapy only, with a median survival of approximately 19 to 25 months.
Similar findings specific to soft-tissue sarcoma were seen at Memorial Sloan-Kettering Cancer Center, where 719 patients with lung metastases from soft-tissue sarcoma were evaluated. The median survival for patients who had undergone complete resection was 33 months, compared with 11 months for those patients treated with nonoperative therapy. The investigators also showed that the disease-free interval and, most importantly, resectability had significant roles in survival. A group at MD Anderson Cancer Center had similar findings: a median survival of 25 months was seen after complete resection vs 6 months in unresectable disease. The MD Anderson investigators also found that the number of nodules detected by preoperative computed tomography (CT) had significant prognostic value. Although Girard et al also found the number of pulmonary metastases to be a significant prognostic factor, survival rates after metastasectomy were still acceptable with multiple pulmonary metastases. They concluded that, if metastases were fully resectable, the number of lesions should have limited influence on the decision to proceed with resection. A short period of observation to ensure stability was suggested for situations in which numerous lesions are found. Blackmon et al evaluated 234 patients with pulmonary metastases from sarcoma and found a similar median survival—35.5 months. Interestingly, the authors also found that the presence of extrapulmonary metastases resected either previously or synchronously did not appear to decrease survival (median survival, 37.5 months). The current National Comprehensive Cancer Network (NCCN) guidelines for soft-tissue sarcoma recommend a broad range of choices for patients with single-organ metastatic disease: metastasectomy ± chemotherapy ± radiation; chemotherapy alone; stereotactic radiation or external beam radiation alone; or observation.
Osteogenic sarcoma often responds poorly to systemic therapies and rarely spreads to organs other than the lungs. Thus, metastasectomy plays an important role in this particular histology. Outcomes are significantly improved with resection of all sites of disease compared with any other combination of treatments. Bricolli et al have shown that even repeat metastasectomy for recurrent pulmonary lesions yields excellent outcomes, with 3-year and 5-year event-free survivals of 33% and 32%, respectively.
1. Kager L, Zoubek A, Potschger U, et al. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol. 2003;21:2011-8.
2. Coindre JM, Terrier P, Guillou L, et al. Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer. 2001;91:1914-26.
3. Raney RB, Jr., Tefft M, Maurer HM, et al. Disease patterns and survival rate in children with metastatic soft-tissue sarcoma. A report from the Intergroup Rhabdomyosarcoma Study (IRS)-I. Cancer. 1988;
4. Krishnan K, Khanna C, Helman LJ. The molecular biology of pulmonary metastasis. Thorac Surg Clin. 2006;16:115-24.
5. Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410:50-6.
6. Murakami T, Maki W, Cardones AR, et al. Expression of CXC chemokine receptor-4 enhances the pulmonary metastatic potential of murine B16 melanoma cells. Cancer Res. 2002;62:7328-34.
7. Kim RH, Li BD, Chu QD. The role of chemokine receptor CXCR4 in the biologic behavior of human soft tissue sarcoma. Sarcoma. 2011;2011:593708.
8. Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. The International Registry of Lung Metastases. J Thorac Cardiovasc Surg. 1997;113:37-49.
9. Casson AG, Putnam JB, Natarajan G, et al. Five-year survival after pulmonary metastasectomy for adult soft tissue sarcoma. Cancer. 1992;69:662-8.
10. Porter GA, Cantor SB, Walsh GL, et al. Cost-effectiveness 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;127:1366-72.
11. Billingsley KG, Burt ME, Jara E, et al. Pulmonary metastases from soft tissue sarcoma: analysis of patterns of diseases and postmetastasis survival. Ann Surg. 1999;229:602-10.
12. Girard P, Spaggiari L, Baldeyrou P, et al. Should the number of pulmonary metastases influence the surgical decision? Eur J Cardiothorac Surg. 1997;12:385-91.
13. Blackmon SH, Shah N, Roth JA, et al. Resection of pulmonary and extrapulmonary sarcomatous metastases is associated with long-term survival. Ann Thorac Surg. 2009;88:877-84.
14. von Mehren M, Benjamin RS, Bui MM, et al. NCCN Guidelines: Soft Tissue Sarcoma, Version 2.2011. 1-90. 8-4-0011. National Comprehensive Cancer Network, Inc.
15. Meyers PA, Heller G, Healey JH, et al. Osteogenic sarcoma with clinically detectable metastasis at initial presentation. J Clin Oncol. 1993;11:449-53.
16. Briccoli A, Rocca M, Salone M, et al. Resection of recurrent pulmonary metastases in patients with osteosarcoma. Cancer. 2005;104:1721-5.
17. 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;34:1223-7.
18. Bar-Shalom R, Yefremov N, Guralnik L, et al. Clinical performance of PET/CT in evaluation of cancer: additional value for diagnostic imaging and patient management. J Nucl Med. 2003;44:1200-9.
19. Downey RJ. Surgical treatment of pulmonary metastases. Surg Oncol Clin N Am. 1999;8:341.
20. 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;84:1830-6.
21. Cerfolio RJ, Bryant AS, McCarty TP, Minnich DJ. A prospective study to determine the incidence of non-imaged malignant pulmonary nodules in patients who undergo metastasectomy by thoracotomy with lung palpation. Ann Thorac Surg. 2011;91:1696-700.
22. 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 Thorac Surg. 1996;62:213-6.
23. Petersen RP, Pham D, Burfeind WR, et al. Thoracoscopic lobectomy facilitates the delivery of chemotherapy after resection for lung cancer. Ann Thorac Surg. 2007;83:1245-9.
24. Gossot D, Radu C, Girard P, et al. Resection of pulmonary metastases from sarcoma: can some patients benefit from a less invasive approach? Ann Thorac Surg. 2009;87:238-43.
25. 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;28:864-8.
26. Detterbeck FC, Egan TM. Thoracoscopy using a substernal handport for palpation. Ann Thorac Surg. 2004;78:1031-6.
27. Mineo TC, Ambrogi V, Mineo D, Pompeo E. Transxiphoid hand-assisted videothoracoscopic surgery. Ann Thorac Surg. 2007;83:1978-84.
28. Martini N, McCormack PM. Evolution of the surgical management of pulmonary metastases. Chest Surg Clin N Am. 1998;8:13-27.
29. Putnam JB, Jr., Roth JA. Prognostic indicators in patients with pulmonary metastases. Semin Surg Oncol. 1990;6:291-6.
30. 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;101:376-82.
31. Palussiere J, Italiano A, Descat E, et al. Sarcoma lung metastases treated with percutaneous radiofrequency ablation: results from 29 patients. Ann Surg Oncol. 2011 Jun 3. [Epub ahead of print]
32. van Putte BP, Hendriks JM, Romijn S, et al. Combination chemotherapy with gemcitabine with isolated lung perfusion for the treatment of pulmonary metastases. J Thorac Cardiovasc Surg. 2005;130:125-30.
33. Burt ME, Liu D, Abolhoda A, et al. Isolated lung perfusion for patients with unresectable metastases from sarcoma: a phase I trial. Ann Thorac Surg. 2000;69:1542-9.
34. The International Registry of Lung Metastases Writing Committee: Pastorino U, Buyse M, FRiedel G, et al. Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. J Thor Cardiovasc Surg. 1997;113:37-49.