Original Article
Pulmonary metastasectomy: Review of experience at a tertiary cancer care center ABSTRACT Background: Thirty to 40% of all extra thoracic cancers lead to secondary pulmonary lesions and approximately 20% of these cases feature metastases that are confined to the lungs. There is benefit of pulmonary metastasectomy in a select subset of patients. Aims: The goal of this study was to evaluate the patient profile, treatment patterns, and outcomes following surgical treatment of lung metastasis and to identify prognostic factors for long‑term survival. Materials and Methods: Retrospective analysis of a prospectively maintained computerized database at a tertiary cancer care centre was done. 36 patients underwent curative resection for isolated pulmonary metastasis from January 1999 to December 2009. All metastasis were detected by non‑contrast CT scan of the chest. Lung function tests were performed in all patients. Posterolateral thoracotomy was performed for resection of pulmonary metastasis by lung sparing procedures. A routine protocol of complete resection of all visible and palpable lung metastasis with a margin of 0.5 to 10 mm was followed in all patients. Staged thoracotomy was done for bilateral metastases. All palpable nodules were resected by wedge resection except in one case where pneumonectomy was done to achieve R0 resection. All patients underwent complete resection. Conclusions: Disease‑free interval of more than 1 year along with less than 2 malignant nodules in patients with non‑visceral pulmonary metastasis are variables identified in the present study which have enabled pulmonary metastasectomy to be offered as a safe therapeutic lifeline to patients. KEY WORDS: Pulmonary metastasis, disease‑free interval, metachronous, metastasectomy, number of nodules
INTRODUCTION Lung is the second most common site of metastasis in solid tumors.[1] Thirty to 40% of all extra thoracic cancers lead to secondary pulmonary lesions during the course of the disease, and approximately 20% of these cases feature metastases that are confined to the lungs.[2] Lung is the only site of metastatic disease in 80% of sarcomas and 2‑10% of carcinomas.[1] Few autopsy series have reported that many patients dying with pulmonary metastatic disease are found to have no extra‑thoracic metastasis.[3] The molecular basis of exclusive pulmonary metastasis is still the subject of intense research. Symptomatic presentation is seen in 15‑20% of patients with pulmonary metastasis.[1] Cough and non‑specific chest pain are the most common symptoms. Majority of patients are asymptomatic when diagnosed with pulmonary metastasis on imaging. Pulmonary metastasis signifies terminal systemic disease in a patient, hence chemotherapy had been the mainstay of therapeutic intervention in majority
of cases. However, as early as 1920, with the anecdotal success of pulmonary metastasectomy in a subsequently diagnosed renal cell carcinoma,[4] surgical resection of pulmonary metastasis was being evaluated as a therapeutic intervention. Lack of effective chemotherapeutic drugs along with better survival in patients with non‑visceral pulmonary metastasis resulted in focused studies, with strict inclusion criteria, being done over the next 5 decades.[5] Published literature from these studies is showing survival advantage in a select group of patients with non‑visceral pulmonary metastasis who otherwise had a dismal prognosis.[6‑9] Pulmonary metastasectomy is currently indicated for patients with following criteria: Primary tumor controlled with no evidence of metastasis outside the lung parenchyma, possibility of complete resection as verified by chest imaging, pulmonary function compatible with the proposed lung resection procedure, and as an extended indication the lack of other more effective treatment.[10] Using these criteria several retrospective series have reported five year survival ranging from 30%-40%.[2]
Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3
Suryanarayana S.V. Deo, Nootan Kumar Shukla, Paras Khanna, Deepak Jha, Archit Pandit, Sanjay Thulkar1 Departments of Surgical Oncology and 1Radiodiagnosis, Dr BRA‑IRCH, AIIMS, New Delhi, India For correspondence: Dr. Paras Khanna, Departments of Surgical Oncology, Dr BRA‑IRCH, AIIMS, New Delhi, India. E‑mail: drparaskhanna@ rediffmail.com
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.139153 PMID: *** Quick Response Code:
535
Deo, et al.: Pulmonary Metastasectomy
There is a growing consensus regarding the benefit of pulmonary metastasectomy in a select subset of patients but there is paucity of literature from the Indian subcontinent. Literature search suggests limited studies have been published sharing the experience of pulmonary metastasectomy from India.[11,12] The differences in presentation and disease biology of cancers such as colorectal and other primaries creates a heterogeneous and different cohort of patients being offered pulmonary metastasectomy in India when compared with western literature. The goal of this study was to evaluate the patient profile, treatment patterns, and outcomes following the surgical treatment of lung metastasis as well as to identify prognostic factors that may significantly impact long‑term survival in patients treated at a single, tertiary care cancer centre. MATERIALS AND METHODS Retrospective analysis of a prospectively maintained computerized database of medical records at a tertiary cancer care centre showed 36 patients who underwent curative resection for isolated pulmonary metastasis from January 1999 to December 2009. Patients were evaluated both for operability and resectability and only those with exclusive non‑visceral pulmonary metastasis, primary under control, resectable pulmonary disease, good post resection pulmonary reserve and favourable histology were included in the study. All metastasis were detected by non‑contrast CT scan of the chest. After ruling out extra pulmonary disease by performing other relevant imaging, lung function tests were performed in all patients. In all patients, under general anesthesia and single lung ventilation either using a double lumen tube or a bronchial blocker, a posterolateral thoracotomy was performed for resection of pulmonary metastasis by lung sparing procedures. A routine protocol of complete resection of all visible and palpable lung metastasis with a margin of 0.5 to 10 mm was followed in all patients. In the case of bilateral nodules, a staged thoracotomy was performed starting on the side with the lowest likelihood of a complete resection. During surgery deflated lungs were methodically palpated by the operating surgeon to look for occult metastasis. All palpable nodules were resected by wedge resection except in one case where pneumonectomy was done to achieve R0 resection. All patients underwent complete resection.
CT scan in recording number of metastatic pulmonary nodules was assessed by using histopathological reporting of resected nodules as the gold standard. DFI‑1 was defined as duration from the resection of the primary tumor to the initial detection of the pulmonary metastasis; DFI‑2 was defined as duration from the first pulmonary metastasectomy to the diagnosis of the recurrent pulmonary metastasis. Synchronous lesions were defined as pulmonary metastasis present at the time of detection of the primary and metachronous lesions were defined as those developing after the treatment of the primary. Overall survival (OS) was defined as time between the registration of the patient to the date of last follow‑up or death. Post metastasectomy survival was defined as the time from metastasectomy to the last follow up or event. RESULTS A total of 36 patients underwent pulmonary metastasectomy during 1999‑2009 [Table 1]. Males with a mean age of 30 years constituted 86.1% of patients. Primary tumor histology was osteosarcoma or soft tissue sarcoma in 80% of the patients. Metachronous presentation of the pulmonary metastasis was seen in 75% of patients with an equal distribution of unilateral and bilateral pulmonary metastasis, in all 54 pulmonary metastasectomy were performed. Diagnosis of pulmonary metastasis was based on CT imaging of the thorax. A total of 29 patients had metastatic nodules located peripherally, 3 had centrally located nodule, and 4 patients had metastatic nodules at both locations. In more than half the cases, CT under or over reported the number of nodules. Lung sparing procedures were performed with ease in all patients except one, who required pneumonectomy for complete resection due to deep seated centrally located metastasis. Stapled wedge resection was performed with GIA linear stapler in 24 patients and hand sewn resection was performed in 10 patients and both were used in 2 patients. On histopathological analysis, 80% of CT detected nodules had metastatic deposits. Most patients were discharged by the fifth postoperative day (length of stay in hospital range 2‑27 days, median 4 days). The postoperative complication rate/morbidity was 2.7% for thoracotomies, and the 30‑day mortality rate was 0%.
For chemosensitive tumors, post‑metastasectomy chemotherapy was planned in a multidisciplinary setting. After treatment completion all patients were kept under close clinical follow‑up which included periodic chest imaging.
Survival characteristics were available for 34 of the 36 patients [Table 2]. Average follow‑up time for all patients was 49.2 months with a range of follow up of 14‑132 months. Mean survival post metastasectomy for these patients (PMOS) was 24 months with patients alive without disease expectedly doing better (35.6 months) than patients alive with disease (14.3 months).
Demographics, clinical and imaging details, surgical procedure, outcomes, and survival data were analysed. Accuracy of chest
A univariate analysis of age, timing, laterality of pulmonary metastasis and primary tumor histology
536
Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3
Deo, et al.: Pulmonary Metastasectomy
Table 1: Clinical characteristics Variables Gender Male Female Primary Osteosarcoma Soft tissue sarcoma Colorectal Germ cell tumor Adrenocortical Giant cell tumor Pulmonary metastasis Unilateral Bilateral Timing Synchronous Metachronous Patients with complete data Alive and disease free Alive with disease Death Lost to follow up
n
%
31 05
86.1 13.9
16 14 3 1 1 1
44.4 38.9 8.3
18 18
50 50
09 27 34/36 14/36 8/36 12/36 2/36
25 75 94.4 38.9 22.2 33.3 5.5
8.3
Table 2: Survival data Total patients Alive and disease free Alive with disease
n 34 14 8
DFI1 22.72 26.9 15.5
DFI2 16.88 29 7.4
PMOS 24.45 35.6 14.4
OS 49.26 63 30.9
showed no statistical difference in patient survival. For OS DFI >12 months (P value 0.005) and pulmonary metastasis less than 2 (P value 0.009) and for PMOS pulmonary metastasis less than 2 (P value 0.015) emerged as statistically significant. All other factors evaluated in the univariate analyses, including age less than or more than 30, primary histology, synchronous vs. metachronous presentation, bilateral or unilateral metastasis in an individual patient, were not statistically significant (P > 0.05) but showed trend towards improvement in OS or PMOS. DISCUSSION Traditionally the presence of pulmonary metastasis signifies systemic spread and also heralds the succumbing of patient to cancer. The earliest historical references of pulmonary metastasectomy were in the era of ineffective chemotherapy where radical surgery was the last resort in “salvaging” young fit cancer patients.[13] Metastasectomy was used selectively for occasional use in solitary relapses over many years in absence of any evidence based guidelines and lack of better options.[14] Pulmonary metastasectomy receded into the background briefly in face of early gains in treating pulmonary metastasis patients with new emerging chemotherapeutic agents. However, ineffective chemotherapy, continuing presentation of young patients with exclusive pulmonary metastasis and some very long‑term survivors ensured a place for surgery in managing selected patients.[15] Only few centres were applying metastasectomy in a systematic way to manage multiple or bilateral pulmonary
metastasis therefore the curative potential of metastasectomy had been recognized slowly.[16,17] The establishment of the International Registry of Lung Metastasis (IRLM) and intense research on the molecular basis of exclusive pulmonary metastasis has brought the spotlight back on pulmonary metastasectomy as a safe therapeutic intervention in eligible patients.[18] In the present study, only 36 patients in a 15‑year period were found eligible for pulmonary metastasectomy. This highlights the fact that in the Indian setup even in a busy tertiary care cancer centre very few patients meet up the strict inclusion criteria of pulmonary metastasectomy. Patients who may be candidates for therapeutic pulmonary metastasectomy represent a very small fraction of those patients with a recurrent malignancy.[19] Young males with an average age of 23 years constituted the overwhelming majority (86%) in the current study. Eckersberger et al., reported male preponderance (65%) in their series with average age of 46 years,[20] whereas in the IRLM males constituted 56% with average age of patients 44 years.[18] The younger age and male sex predominance of patients in the present study is not only due to the disproportionate number of sarcomas (83%) but probably also underscore the fact that a selection bias results in the most fit patients being selected for metastasectomy. Bilateral presentation seen in 50% of patients is higher than reported in the IRLM (11%),[18] though >40% bilateral cases were also reported by Younes RN et al.[21] Selected patients were taken up for staged metastasectomy. The selection of patients with bilateral disease for metastasectomy is well supported in literature as long as R‑O resection can be achieved.[20,22] In the current study, 25% patients presented with synchronous pulmonary metastasis. These patients did worse than patients with metachronous pulmonary metastasis that had longer overall (53 vs. 37 months) and postmetastasectomy survival (25 and 21 months), which however did not achieve statistical significance. Putman et al.,[23] and the IRLM[18] have indeed associated DFI with better survival taking cut offs at 12 or 36 months. However, there is inconsistency in literature with regards synchronous lung metastasis especially in osteosarcoma and soft tissue sarcoma series.[24] Concordance of CT detected nodules and operative findings have been variably reported as 27‑40%.[18,25] Because of the discrepancy between what is seen radiographically and what is found at surgery, it is important to distinguish between the number of nodules seen preoperatively and the number of metastases found pathologically in the resected specimens. In the present study, CT concordance was seen in 47.2%, over reporting in 5.6% of patients and underreporting in 47.2% of patients. Several reports have demonstrated the prognostic importance of the number of nodules,[2,18] though there seems to be no
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reason to abort a metastasectomy operation no matter how many metastases are found intraoperatively as long as a complete resection can be accomplished and the patient can tolerate the procedure.[26] Reports from the IRLM divide the cases according to the primary malignancies and show a general rule that survival depends on the number of metastases.[18] In the present study patients with less than 2 malignant nodules did better and this difference was statistically significant. The number of metastases is a reflection of the degree of dissemination of the cancer and a consistent measure of the biologic aggressiveness of a cancer hence number of nodules has been repeatedly shown to achieve statistical significance in published literature.[27] Majority of cases in Western series on pulmonary metastasectomy are colorectal.[9] However, in the Indian population as a result of relative rarity and different disease biology of colorectal cancers the predominant histology of patients with resectable pulmonary metastasis is osteosarcoma and soft tissue sarcoma. In the current study, survival rates were significantly better for patients with soft tissue sarcoma when compared to osteosarcoma. There is inconsistency in published literature with regards prognostic value of primary histology. Eckersberger et al., report better survival in osteosarcoma patients,[20] but Turney et al., found better survival in sarcoma.[28] Complete R‑O resection was achieved in all patients in the present study with posterolateral thoracotomy and meticulous palpation for invisible nodules. Low post‑operative morbidity (2.7%) and no mortality highlight the safety of metastasectomy as reported in literature.[18] In the current study, DFI more than 12 months and pulmonary nodules less than 2 were good prognostic factors. PMOS was significantly better for patients with a DFI of more than a year as has been reported by Billingsley et al.,[29] IRLM,[18] among others.[23] Small numbers and retrospective nature of the present study has precluded statistical significance of some important trends but this has been the problem with majority of pulmonary metastasectomy series. CONCLUSION Determination of prognostic factors is an attempt to identify patient groups with the greatest potential profit from metastasectomy. That only 36 patients were found eligible in a 15‑year period goes on to underscore that very few patients were found fit and eligible for the procedure. The fundamental biology of these cancers and the genetic factors governing metastasis are still undefined, so the criteria used in selecting patients for pulmonary resection are clinical, and hence, relatively imprecise. A disease‑free interval of more than 1 year along with less than 2 malignant nodules in patients with non‑visceral pulmonary metastasis are variables identified in the present study, which have enabled pulmonary 538
metastasectomy to be offered as a safe therapeutic lifeline to patients who had reached the dead end of cancer treatment. REFERENCES 1. Valerie W. Rusch. Lung Metastasis. In: Martin D. Abeloff, editor. Abeloff’s Clinical Oncology, 4th ed. Philadelphia: Churchill Livingstone; 2008. p. 873‑84. 2. Pastorino U. Lung metastasectomy: Why, when, how. Crit Rev Oncol Hematol 1997;26:137‑45. 3. Todd TR. The surgical treatment of pulmonary metastases. Chest 1997;112:287S‑290S. 4. Barney JE, Churchill EJ. Adenocarcinoma of the kidney with metastases to the lung. J Urol 1939;42:269‑76. 5. McCormack PM, Martini N. The changing role of surgery for pulmonary metastases. Ann Thorac Surg 1979;28:139‑45. 6. Ris HB, Vorburger T, Noce R, Maibach R, Stirnemann P, Nachbur B, et al. Surgery and chemotherapy for pulmonary metastases: Long term results from a combined modality approach. Thorac Cardiovasc Surg 1991;39:224‑7. 7. Mountain CF, McMurtrey MJ, Hermes KE. Surgery for pulmonary metastases: A 20 year experience. Ann Thorac Surg 1984;38:323‑30. 8. Marincola FM, Mark JB. Selection factors resulting in improved survival after surgical resection of tumors metastatic to the lungs. Arch Surg 1990;125:1387‑92. 9. Girard P, Baldeyrou P, Le Chevalier T, Le Cesne A, Brigandi A, Grunenwald D. Surgery for pulmonary metastases. Who are the 10‑year survivors? Cancer 1994;74:2791‑7. 10. Martini N, McCormack PM. Evolution of the surgical management of pulmonary metastases. Chest Surg Clin N Am 1998;8:13‑27. 11. Viswanathan S, Jambhekar NA. Metastatic giant cell tumor of bone: Are there associated factors and best treatment modalities? Clin Orthop Relat Res 2010;468:827‑33. 12. Ramakrishnan AS, Velusamy S, Sundersingh S, Mahajan V. Pulmonary metastasectomy for uterine malignant mixed mullerian tumor. J Obstet Gynecol India 2010;60:77‑8. 13. Edwards AT. Malignant disease of the lung. J Thorac Surg 1934;4:107-24. 14. Pastorino U, Treasure T. A historical note on pulmonary metastasectomy. J Thorac Oncol 2010;5:S132‑3. 15. Putnam JB Jr, Roth JA, Wesley MN, Johnston MR, Rosenberg SA Survival following aggressive resection of pulmonary metastases from osteogenic sarcoma: Analysis of prognostic factors. Ann Thorac Surg 1983;36:516‑23. 16. Martini N, Huvos AG, Miké V, Marcove RC, Beattie EJ Jr. Multiple pulmonary resections in the treatment of osteogenic sarcoma. Ann Thorac Surg 1971;12:271‑80. 17. Beattie EJ, Harvey JC, Marcove R, Martini N. Results of multiple pulmonary resections for metastatic osteogenic sarcoma after two decades. J Surg Oncol 1991;46:154‑5. 18. Friedel G, Pastorino U, Buyse M, Ginsberg RJ, Girard P, Goldstraw P, et al. Resection of lung metastases: Long‑term results and prognostic analysis based on 5206 cases‑the International Registry of Lung Metastases. Zentralbl Chir 1999;124:96‑103. 19. Patel AN, Lamb J, Patel N, Santos RS, Stavropoulos C, Landreneau RJ. Clinical Trials for Pulmonary Metastasectomy. Semin Thorac Cardiovasc Surg 2003;15:457‑63. 20. Eckersberger F, Moritz E, Wolner E. Results and prognostic factors after resection of pulmonary metastases. Eur J Cardiothorac Surg 1988;2:433‑7. 21. Younes RN, Gross JL, Taira AM, Martins AA, Neves GS. Surgical resection of lung metastases: Results from 529 patients. Clinics (Sao Paulo) 2009;64:535‑41. 22. Pastorino U, Valente M, Gasparini M, Azzarelli A, Santoro A, Tavecchio L, et al. Lung resection as salvage treatment for metastatic osteosarcoma. Tumori 1988;74:201‑6.
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23. Putnam JB Jr, Roth JA. Prognostic indicators in patients with pulmonary metastases. Semin Surg Oncol 1990;6:291‑6. 24. Bacci G, Briccoli A, Picci P. Osteosarcoma of the extremities metastatic at presentation: Results achieved in 26 patients treated with combined therapy (primary chemotherapy followed by simultaneous resection of the primary and metastatic lesions). Tumori 1992;78:200‑6. 25. Friedmann G, Bohndorf K, Krüger J. Radiology of pulmonary metastases: Comparison of imaging techniques with operative findings. Thorac Cardiovasc Surg 1986;34:120‑4. 26. Detterbeck F. The Number of Metastases and Its Influence on Outcome. Editorial Comment. J Thorac Oncol 2010;5:S164‑5. 27. García‑Yuste M, Cassivi S, Paleru C. The Number of Pulmonary
Metastases: Influence on Practice and Outcome. J Thorac Oncol 2010;5:S161‑3. 28. Turney SZ, Haight C. Pulmonary resection for metastatic neoplasms. J Thorac Cardiovasc Surg 1971;61:784‑94. 29. Billingsley KG, Burt ME, Jara E, Ginsberg RJ, Woodruff JM, Leung DH, et al. Pulmonary metastases from soft tissue sarcoma: Analysis of patterns of diseases and postmetastasis survival. Ann Surg 1999;229:602‑12. Cite this article as: Deo SS, Shukla NK, Khanna P, Jha D, Pandit A, Thulkar S. Pulmonary metastasectomy: Review of experience at a tertiary cancer care center. J Can Res Ther 2014;10:535-9. Source of Support: Nil, Conflict of Interest: None declared.
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Pulmonary metastasectomy: Review of experience at a tertiary cancer care center ABSTRACT Background: Thirty to 40% of all extra thoracic cancers lead to secondary pulmonary lesions and approximately 20% of these cases feature metastases that are confined to the lungs. There is benefit of pulmonary metastasectomy in a select subset of patients. Aims: The goal of this study was to evaluate the patient profile, treatment patterns, and outcomes following surgical treatment of lung metastasis and to identify prognostic factors for long‑term survival. Materials and Methods: Retrospective analysis of a prospectively maintained computerized database at a tertiary cancer care centre was done. 36 patients underwent curative resection for isolated pulmonary metastasis from January 1999 to December 2009. All metastasis were detected by non‑contrast CT scan of the chest. Lung function tests were performed in all patients. Posterolateral thoracotomy was performed for resection of pulmonary metastasis by lung sparing procedures. A routine protocol of complete resection of all visible and palpable lung metastasis with a margin of 0.5 to 10 mm was followed in all patients. Staged thoracotomy was done for bilateral metastases. All palpable nodules were resected by wedge resection except in one case where pneumonectomy was done to achieve R0 resection. All patients underwent complete resection. Conclusions: Disease‑free interval of more than 1 year along with less than 2 malignant nodules in patients with non‑visceral pulmonary metastasis are variables identified in the present study which have enabled pulmonary metastasectomy to be offered as a safe therapeutic lifeline to patients. KEY WORDS: Pulmonary metastasis, disease‑free interval, metachronous, metastasectomy, number of nodules
INTRODUCTION Lung is the second most common site of metastasis in solid tumors.[1] Thirty to 40% of all extra thoracic cancers lead to secondary pulmonary lesions during the course of the disease, and approximately 20% of these cases feature metastases that are confined to the lungs.[2] Lung is the only site of metastatic disease in 80% of sarcomas and 2‑10% of carcinomas.[1] Few autopsy series have reported that many patients dying with pulmonary metastatic disease are found to have no extra‑thoracic metastasis.[3] The molecular basis of exclusive pulmonary metastasis is still the subject of intense research. Symptomatic presentation is seen in 15‑20% of patients with pulmonary metastasis.[1] Cough and non‑specific chest pain are the most common symptoms. Majority of patients are asymptomatic when diagnosed with pulmonary metastasis on imaging. Pulmonary metastasis signifies terminal systemic disease in a patient, hence chemotherapy had been the mainstay of therapeutic intervention in majority
of cases. However, as early as 1920, with the anecdotal success of pulmonary metastasectomy in a subsequently diagnosed renal cell carcinoma,[4] surgical resection of pulmonary metastasis was being evaluated as a therapeutic intervention. Lack of effective chemotherapeutic drugs along with better survival in patients with non‑visceral pulmonary metastasis resulted in focused studies, with strict inclusion criteria, being done over the next 5 decades.[5] Published literature from these studies is showing survival advantage in a select group of patients with non‑visceral pulmonary metastasis who otherwise had a dismal prognosis.[6‑9] Pulmonary metastasectomy is currently indicated for patients with following criteria: Primary tumor controlled with no evidence of metastasis outside the lung parenchyma, possibility of complete resection as verified by chest imaging, pulmonary function compatible with the proposed lung resection procedure, and as an extended indication the lack of other more effective treatment.[10] Using these criteria several retrospective series have reported five year survival ranging from 30%-40%.[2]
Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3
Suryanarayana S.V. Deo, Nootan Kumar Shukla, Paras Khanna, Deepak Jha, Archit Pandit, Sanjay Thulkar1 Departments of Surgical Oncology and 1Radiodiagnosis, Dr BRA‑IRCH, AIIMS, New Delhi, India For correspondence: Dr. Paras Khanna, Departments of Surgical Oncology, Dr BRA‑IRCH, AIIMS, New Delhi, India. E‑mail: drparaskhanna@ rediffmail.com
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.139153 PMID: *** Quick Response Code:
535
Deo, et al.: Pulmonary Metastasectomy
There is a growing consensus regarding the benefit of pulmonary metastasectomy in a select subset of patients but there is paucity of literature from the Indian subcontinent. Literature search suggests limited studies have been published sharing the experience of pulmonary metastasectomy from India.[11,12] The differences in presentation and disease biology of cancers such as colorectal and other primaries creates a heterogeneous and different cohort of patients being offered pulmonary metastasectomy in India when compared with western literature. The goal of this study was to evaluate the patient profile, treatment patterns, and outcomes following the surgical treatment of lung metastasis as well as to identify prognostic factors that may significantly impact long‑term survival in patients treated at a single, tertiary care cancer centre. MATERIALS AND METHODS Retrospective analysis of a prospectively maintained computerized database of medical records at a tertiary cancer care centre showed 36 patients who underwent curative resection for isolated pulmonary metastasis from January 1999 to December 2009. Patients were evaluated both for operability and resectability and only those with exclusive non‑visceral pulmonary metastasis, primary under control, resectable pulmonary disease, good post resection pulmonary reserve and favourable histology were included in the study. All metastasis were detected by non‑contrast CT scan of the chest. After ruling out extra pulmonary disease by performing other relevant imaging, lung function tests were performed in all patients. In all patients, under general anesthesia and single lung ventilation either using a double lumen tube or a bronchial blocker, a posterolateral thoracotomy was performed for resection of pulmonary metastasis by lung sparing procedures. A routine protocol of complete resection of all visible and palpable lung metastasis with a margin of 0.5 to 10 mm was followed in all patients. In the case of bilateral nodules, a staged thoracotomy was performed starting on the side with the lowest likelihood of a complete resection. During surgery deflated lungs were methodically palpated by the operating surgeon to look for occult metastasis. All palpable nodules were resected by wedge resection except in one case where pneumonectomy was done to achieve R0 resection. All patients underwent complete resection.
CT scan in recording number of metastatic pulmonary nodules was assessed by using histopathological reporting of resected nodules as the gold standard. DFI‑1 was defined as duration from the resection of the primary tumor to the initial detection of the pulmonary metastasis; DFI‑2 was defined as duration from the first pulmonary metastasectomy to the diagnosis of the recurrent pulmonary metastasis. Synchronous lesions were defined as pulmonary metastasis present at the time of detection of the primary and metachronous lesions were defined as those developing after the treatment of the primary. Overall survival (OS) was defined as time between the registration of the patient to the date of last follow‑up or death. Post metastasectomy survival was defined as the time from metastasectomy to the last follow up or event. RESULTS A total of 36 patients underwent pulmonary metastasectomy during 1999‑2009 [Table 1]. Males with a mean age of 30 years constituted 86.1% of patients. Primary tumor histology was osteosarcoma or soft tissue sarcoma in 80% of the patients. Metachronous presentation of the pulmonary metastasis was seen in 75% of patients with an equal distribution of unilateral and bilateral pulmonary metastasis, in all 54 pulmonary metastasectomy were performed. Diagnosis of pulmonary metastasis was based on CT imaging of the thorax. A total of 29 patients had metastatic nodules located peripherally, 3 had centrally located nodule, and 4 patients had metastatic nodules at both locations. In more than half the cases, CT under or over reported the number of nodules. Lung sparing procedures were performed with ease in all patients except one, who required pneumonectomy for complete resection due to deep seated centrally located metastasis. Stapled wedge resection was performed with GIA linear stapler in 24 patients and hand sewn resection was performed in 10 patients and both were used in 2 patients. On histopathological analysis, 80% of CT detected nodules had metastatic deposits. Most patients were discharged by the fifth postoperative day (length of stay in hospital range 2‑27 days, median 4 days). The postoperative complication rate/morbidity was 2.7% for thoracotomies, and the 30‑day mortality rate was 0%.
For chemosensitive tumors, post‑metastasectomy chemotherapy was planned in a multidisciplinary setting. After treatment completion all patients were kept under close clinical follow‑up which included periodic chest imaging.
Survival characteristics were available for 34 of the 36 patients [Table 2]. Average follow‑up time for all patients was 49.2 months with a range of follow up of 14‑132 months. Mean survival post metastasectomy for these patients (PMOS) was 24 months with patients alive without disease expectedly doing better (35.6 months) than patients alive with disease (14.3 months).
Demographics, clinical and imaging details, surgical procedure, outcomes, and survival data were analysed. Accuracy of chest
A univariate analysis of age, timing, laterality of pulmonary metastasis and primary tumor histology
536
Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3
Deo, et al.: Pulmonary Metastasectomy
Table 1: Clinical characteristics Variables Gender Male Female Primary Osteosarcoma Soft tissue sarcoma Colorectal Germ cell tumor Adrenocortical Giant cell tumor Pulmonary metastasis Unilateral Bilateral Timing Synchronous Metachronous Patients with complete data Alive and disease free Alive with disease Death Lost to follow up
n
%
31 05
86.1 13.9
16 14 3 1 1 1
44.4 38.9 8.3
18 18
50 50
09 27 34/36 14/36 8/36 12/36 2/36
25 75 94.4 38.9 22.2 33.3 5.5
8.3
Table 2: Survival data Total patients Alive and disease free Alive with disease
n 34 14 8
DFI1 22.72 26.9 15.5
DFI2 16.88 29 7.4
PMOS 24.45 35.6 14.4
OS 49.26 63 30.9
showed no statistical difference in patient survival. For OS DFI >12 months (P value 0.005) and pulmonary metastasis less than 2 (P value 0.009) and for PMOS pulmonary metastasis less than 2 (P value 0.015) emerged as statistically significant. All other factors evaluated in the univariate analyses, including age less than or more than 30, primary histology, synchronous vs. metachronous presentation, bilateral or unilateral metastasis in an individual patient, were not statistically significant (P > 0.05) but showed trend towards improvement in OS or PMOS. DISCUSSION Traditionally the presence of pulmonary metastasis signifies systemic spread and also heralds the succumbing of patient to cancer. The earliest historical references of pulmonary metastasectomy were in the era of ineffective chemotherapy where radical surgery was the last resort in “salvaging” young fit cancer patients.[13] Metastasectomy was used selectively for occasional use in solitary relapses over many years in absence of any evidence based guidelines and lack of better options.[14] Pulmonary metastasectomy receded into the background briefly in face of early gains in treating pulmonary metastasis patients with new emerging chemotherapeutic agents. However, ineffective chemotherapy, continuing presentation of young patients with exclusive pulmonary metastasis and some very long‑term survivors ensured a place for surgery in managing selected patients.[15] Only few centres were applying metastasectomy in a systematic way to manage multiple or bilateral pulmonary
metastasis therefore the curative potential of metastasectomy had been recognized slowly.[16,17] The establishment of the International Registry of Lung Metastasis (IRLM) and intense research on the molecular basis of exclusive pulmonary metastasis has brought the spotlight back on pulmonary metastasectomy as a safe therapeutic intervention in eligible patients.[18] In the present study, only 36 patients in a 15‑year period were found eligible for pulmonary metastasectomy. This highlights the fact that in the Indian setup even in a busy tertiary care cancer centre very few patients meet up the strict inclusion criteria of pulmonary metastasectomy. Patients who may be candidates for therapeutic pulmonary metastasectomy represent a very small fraction of those patients with a recurrent malignancy.[19] Young males with an average age of 23 years constituted the overwhelming majority (86%) in the current study. Eckersberger et al., reported male preponderance (65%) in their series with average age of 46 years,[20] whereas in the IRLM males constituted 56% with average age of patients 44 years.[18] The younger age and male sex predominance of patients in the present study is not only due to the disproportionate number of sarcomas (83%) but probably also underscore the fact that a selection bias results in the most fit patients being selected for metastasectomy. Bilateral presentation seen in 50% of patients is higher than reported in the IRLM (11%),[18] though >40% bilateral cases were also reported by Younes RN et al.[21] Selected patients were taken up for staged metastasectomy. The selection of patients with bilateral disease for metastasectomy is well supported in literature as long as R‑O resection can be achieved.[20,22] In the current study, 25% patients presented with synchronous pulmonary metastasis. These patients did worse than patients with metachronous pulmonary metastasis that had longer overall (53 vs. 37 months) and postmetastasectomy survival (25 and 21 months), which however did not achieve statistical significance. Putman et al.,[23] and the IRLM[18] have indeed associated DFI with better survival taking cut offs at 12 or 36 months. However, there is inconsistency in literature with regards synchronous lung metastasis especially in osteosarcoma and soft tissue sarcoma series.[24] Concordance of CT detected nodules and operative findings have been variably reported as 27‑40%.[18,25] Because of the discrepancy between what is seen radiographically and what is found at surgery, it is important to distinguish between the number of nodules seen preoperatively and the number of metastases found pathologically in the resected specimens. In the present study, CT concordance was seen in 47.2%, over reporting in 5.6% of patients and underreporting in 47.2% of patients. Several reports have demonstrated the prognostic importance of the number of nodules,[2,18] though there seems to be no
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reason to abort a metastasectomy operation no matter how many metastases are found intraoperatively as long as a complete resection can be accomplished and the patient can tolerate the procedure.[26] Reports from the IRLM divide the cases according to the primary malignancies and show a general rule that survival depends on the number of metastases.[18] In the present study patients with less than 2 malignant nodules did better and this difference was statistically significant. The number of metastases is a reflection of the degree of dissemination of the cancer and a consistent measure of the biologic aggressiveness of a cancer hence number of nodules has been repeatedly shown to achieve statistical significance in published literature.[27] Majority of cases in Western series on pulmonary metastasectomy are colorectal.[9] However, in the Indian population as a result of relative rarity and different disease biology of colorectal cancers the predominant histology of patients with resectable pulmonary metastasis is osteosarcoma and soft tissue sarcoma. In the current study, survival rates were significantly better for patients with soft tissue sarcoma when compared to osteosarcoma. There is inconsistency in published literature with regards prognostic value of primary histology. Eckersberger et al., report better survival in osteosarcoma patients,[20] but Turney et al., found better survival in sarcoma.[28] Complete R‑O resection was achieved in all patients in the present study with posterolateral thoracotomy and meticulous palpation for invisible nodules. Low post‑operative morbidity (2.7%) and no mortality highlight the safety of metastasectomy as reported in literature.[18] In the current study, DFI more than 12 months and pulmonary nodules less than 2 were good prognostic factors. PMOS was significantly better for patients with a DFI of more than a year as has been reported by Billingsley et al.,[29] IRLM,[18] among others.[23] Small numbers and retrospective nature of the present study has precluded statistical significance of some important trends but this has been the problem with majority of pulmonary metastasectomy series. CONCLUSION Determination of prognostic factors is an attempt to identify patient groups with the greatest potential profit from metastasectomy. That only 36 patients were found eligible in a 15‑year period goes on to underscore that very few patients were found fit and eligible for the procedure. The fundamental biology of these cancers and the genetic factors governing metastasis are still undefined, so the criteria used in selecting patients for pulmonary resection are clinical, and hence, relatively imprecise. A disease‑free interval of more than 1 year along with less than 2 malignant nodules in patients with non‑visceral pulmonary metastasis are variables identified in the present study, which have enabled pulmonary 538
metastasectomy to be offered as a safe therapeutic lifeline to patients who had reached the dead end of cancer treatment. REFERENCES 1. Valerie W. Rusch. Lung Metastasis. In: Martin D. Abeloff, editor. Abeloff’s Clinical Oncology, 4th ed. Philadelphia: Churchill Livingstone; 2008. p. 873‑84. 2. Pastorino U. Lung metastasectomy: Why, when, how. Crit Rev Oncol Hematol 1997;26:137‑45. 3. Todd TR. The surgical treatment of pulmonary metastases. Chest 1997;112:287S‑290S. 4. Barney JE, Churchill EJ. Adenocarcinoma of the kidney with metastases to the lung. J Urol 1939;42:269‑76. 5. McCormack PM, Martini N. The changing role of surgery for pulmonary metastases. Ann Thorac Surg 1979;28:139‑45. 6. Ris HB, Vorburger T, Noce R, Maibach R, Stirnemann P, Nachbur B, et al. Surgery and chemotherapy for pulmonary metastases: Long term results from a combined modality approach. Thorac Cardiovasc Surg 1991;39:224‑7. 7. Mountain CF, McMurtrey MJ, Hermes KE. Surgery for pulmonary metastases: A 20 year experience. Ann Thorac Surg 1984;38:323‑30. 8. Marincola FM, Mark JB. Selection factors resulting in improved survival after surgical resection of tumors metastatic to the lungs. Arch Surg 1990;125:1387‑92. 9. Girard P, Baldeyrou P, Le Chevalier T, Le Cesne A, Brigandi A, Grunenwald D. Surgery for pulmonary metastases. Who are the 10‑year survivors? Cancer 1994;74:2791‑7. 10. Martini N, McCormack PM. Evolution of the surgical management of pulmonary metastases. Chest Surg Clin N Am 1998;8:13‑27. 11. Viswanathan S, Jambhekar NA. Metastatic giant cell tumor of bone: Are there associated factors and best treatment modalities? Clin Orthop Relat Res 2010;468:827‑33. 12. Ramakrishnan AS, Velusamy S, Sundersingh S, Mahajan V. Pulmonary metastasectomy for uterine malignant mixed mullerian tumor. J Obstet Gynecol India 2010;60:77‑8. 13. Edwards AT. Malignant disease of the lung. J Thorac Surg 1934;4:107-24. 14. Pastorino U, Treasure T. A historical note on pulmonary metastasectomy. J Thorac Oncol 2010;5:S132‑3. 15. Putnam JB Jr, Roth JA, Wesley MN, Johnston MR, Rosenberg SA Survival following aggressive resection of pulmonary metastases from osteogenic sarcoma: Analysis of prognostic factors. Ann Thorac Surg 1983;36:516‑23. 16. Martini N, Huvos AG, Miké V, Marcove RC, Beattie EJ Jr. Multiple pulmonary resections in the treatment of osteogenic sarcoma. Ann Thorac Surg 1971;12:271‑80. 17. Beattie EJ, Harvey JC, Marcove R, Martini N. Results of multiple pulmonary resections for metastatic osteogenic sarcoma after two decades. J Surg Oncol 1991;46:154‑5. 18. Friedel G, Pastorino U, Buyse M, Ginsberg RJ, Girard P, Goldstraw P, et al. Resection of lung metastases: Long‑term results and prognostic analysis based on 5206 cases‑the International Registry of Lung Metastases. Zentralbl Chir 1999;124:96‑103. 19. Patel AN, Lamb J, Patel N, Santos RS, Stavropoulos C, Landreneau RJ. Clinical Trials for Pulmonary Metastasectomy. Semin Thorac Cardiovasc Surg 2003;15:457‑63. 20. Eckersberger F, Moritz E, Wolner E. Results and prognostic factors after resection of pulmonary metastases. Eur J Cardiothorac Surg 1988;2:433‑7. 21. Younes RN, Gross JL, Taira AM, Martins AA, Neves GS. Surgical resection of lung metastases: Results from 529 patients. Clinics (Sao Paulo) 2009;64:535‑41. 22. Pastorino U, Valente M, Gasparini M, Azzarelli A, Santoro A, Tavecchio L, et al. Lung resection as salvage treatment for metastatic osteosarcoma. Tumori 1988;74:201‑6.
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23. Putnam JB Jr, Roth JA. Prognostic indicators in patients with pulmonary metastases. Semin Surg Oncol 1990;6:291‑6. 24. Bacci G, Briccoli A, Picci P. Osteosarcoma of the extremities metastatic at presentation: Results achieved in 26 patients treated with combined therapy (primary chemotherapy followed by simultaneous resection of the primary and metastatic lesions). Tumori 1992;78:200‑6. 25. Friedmann G, Bohndorf K, Krüger J. Radiology of pulmonary metastases: Comparison of imaging techniques with operative findings. Thorac Cardiovasc Surg 1986;34:120‑4. 26. Detterbeck F. The Number of Metastases and Its Influence on Outcome. Editorial Comment. J Thorac Oncol 2010;5:S164‑5. 27. García‑Yuste M, Cassivi S, Paleru C. The Number of Pulmonary
Metastases: Influence on Practice and Outcome. J Thorac Oncol 2010;5:S161‑3. 28. Turney SZ, Haight C. Pulmonary resection for metastatic neoplasms. J Thorac Cardiovasc Surg 1971;61:784‑94. 29. Billingsley KG, Burt ME, Jara E, Ginsberg RJ, Woodruff JM, Leung DH, et al. Pulmonary metastases from soft tissue sarcoma: Analysis of patterns of diseases and postmetastasis survival. Ann Surg 1999;229:602‑12. Cite this article as: Deo SS, Shukla NK, Khanna P, Jha D, Pandit A, Thulkar S. Pulmonary metastasectomy: Review of experience at a tertiary cancer care center. J Can Res Ther 2014;10:535-9. Source of Support: Nil, Conflict of Interest: None declared.
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