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  Table of Contents  
BONE AND SOFT TISSUES
Year : 2020  |  Volume : 57  |  Issue : 2  |  Page : 172-181
 

Pulmonary metastasectomy in primary extremity osteosarcoma: Choosing wisely, along with a brief review of literature


1 Department of Orthopedic Oncology, Oncology, Cancer Institute (WIA),38, Sardar Patel Rd, Adyar, Chennai, Tamil Nadu, India
2 Department of Surgical Oncology, Cancer Institute (WIA),38, Sardar Patel Rd, Adyar, Chennai, Tamil Nadu, India

Date of Submission27-Jul-2018
Date of Decision22-Sep-2018
Date of Acceptance30-Sep-2018
Date of Web Publication17-May-2020

Correspondence Address:
Arvind Krishnamurthy
Department of Surgical Oncology, Cancer Institute (WIA),38, Sardar Patel Rd, Adyar, Chennai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_497_18

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 » Abstract 


Background: Despite the advances in systemic treatment, about 30%–40% of the patients with extremity osteosarcomas relapse and more than 80% of these relapses localize in the lungs. Our understanding of the management of pulmonary metastases from extremity osteosarcomas is largely based on retrospective data from single institutions or compiled from registries; hence, there is great degree of variability in the reported management of pulmonary metastasis in patients with osteosarcomas.
Aims and objectives: To analyze the demographic profile, disease characteristics and survival outcomes of patients who had undergone potentially curative pulmonary metastasectomies from extremity osteosarcomas.
Materials and methods: Retrospective analysis of the 37 patients with resectable pulmonary metastasis (both synchronous and metachronous) from osteosarcoma of the extremity, treated from January 1, 2003 to December 31, 2017 at a tertiary regional cancer center in South India.
Results: The median overall survival (OS) of our patient cohort was 38 ± 2.7 months. The 2-, 3-, and 5-year OS were 86 ± 5.8%, 60.8 ± 8.6%, and 20.7 ± 7.4%, respectively. A formal analysis of the various prognostic factors revealed disease-free interval >2 years, completion of the planned systemic chemotherapy, and absence of pulmonary recurrence post-metastasectomy to be significantly influencing the survival outcomes.
Conclusion: Our study reiterates the need for consideration of pulmonary metastasectomy in carefully selected patients of extremity osteosarcomas. There is a paucity of data on pulmonary metastasectomies from India and our cohort is possibly the largest series for pulmonary metastasectomies from an osteosarcoma primary. In routine clinical practice, we recommend that the final decision to proceed with pulmonary metastasectomy should ideally be taken by a multidisciplinary tumor board on a case-by-case basis.


Keywords: Extremity osteosarcoma, limb salvage surgery, prognosis, pulmonary metastasectomy


How to cite this article:
Ramanujan V, Krishnamurthy A, Venkataramani K, Kumar C. Pulmonary metastasectomy in primary extremity osteosarcoma: Choosing wisely, along with a brief review of literature. Indian J Cancer 2020;57:172-81

How to cite this URL:
Ramanujan V, Krishnamurthy A, Venkataramani K, Kumar C. Pulmonary metastasectomy in primary extremity osteosarcoma: Choosing wisely, along with a brief review of literature. Indian J Cancer [serial online] 2020 [cited 2020 May 28];57:172-81. Available from: http://www.indianjcancer.com/text.asp?2020/57/2/172/284476





 » Introduction Top


Osteosarcoma is the most common malignant bone tumor in children and young adults. The survival outcome of nonmetastatic extremity osteosarcomas has significantly increased over the years, largely due to the incorporation of multiagent chemotherapy to radical surgery.[1] Despite the advances in systemic treatment, about 30%–40% of extremity osteosarcoma patients relapse and >80% of these relapses localize in the lungs.[2] Further, about 20% of the patients present with metastatic disease at the time of diagnosis; the most common metastatic site is the lungs.[3] Undoubtedly, the preferred method for the management of resectable pulmonary metastases from extremity osteosarcomas is metastasectomy. However, due to the heterogeneity of the available evidences which is largely retrospective, a standardized protocol of management for patients with pulmonary metastases from extremity osteosarcomas has not yet fully evolved. We aimed to study the clinicopathological characteristics and survival outcomes of our patient cohort with pulmonary metastases from extremity osteosarcoma and additionally, briefly review the published literature. There is a paucity of data on pulmonary metastasectomy from India and our cohort is possibly the largest series of pulmonary metastasectomies for any cancer and also specifically from an osteosarcoma primary.


 » Materials and Methods Top


Study design

Retrospective analysis of a prospective cohort.

Setting

This study was conducted at a tertiary regional cancer center in South India. Thirty-seven patients with resectable pulmonary metastasis (both synchronous and metachronous) from osteosarcoma of the extremity were included. The historical records of the eligible patient cohort were reviewed, and all the relevant clinical details including demographic profile histological variants, treatment, and disease outcomes were captured and analyzed.

Inclusion and exclusion criteria

Patients who underwent resection of pulmonary metastasis (synchronous and metachronous) arising from extremity osteosarcoma treated between January 1, 2003 and December 31, 2017 with a potentially curative intent were included. Patients with synchronous metastasis completed systemic chemotherapy and treatment for local disease and their metastasis were addressed in staged setting after completion of protocol chemotherapy. Patients who were managed with a palliative intent were excluded.

Management protocol

All patients with nonmetastatic or resectable metastatic extremity osteosarcoma received neoadjuvant chemotherapy, i.e., usually three cycles of ifosfamide, adriamycin, and cisplatinum (IAP) chemotherapy and underwent surgery for the primary tumor which was followed by completion of the remaining cycles of chemotherapy. Upfront surgery for the primary was contemplated only in patients with grossly displaced pathological fracture at the time of diagnosis. The synchronous metastatic pulmonary lesions were reassessed for resectability after completion of the above treatment. The pulmonary metastasectomy was either a video-assisted thoracoscopic surgery (VATS) or thoracotomy, which was decided by the thoracic surgeons depending on location and size of the metastasis. A few selected patients following pulmonary metastasectomy were considered for second-line methotrexate-based chemotherapy. All the patients were regularly followed up as per standard guidelines and the seminal events pertaining to the survival outcomes were additionally captured.

Outcomes measured

Overall survival (OS) was defined as the time from first detection of lung metastases until the last follow-up or death. Postmetastasectomy survival (PMS) was defined as the time from metastasectomy, until the first documentation of progression or recurrence, last follow-up or death. If patient had bilateral metastases, the postmetastasectomy survival was calculated from the date of last metastasectomy. Progression was defined as the appearance of one or more new lesions or an increases in the size of target measurable lesions of ≥20% of the sum of the longest diameters by response evaluation in solid tumor criteria.

Statistical analysis

Baseline characteristics were collected and entered in spread sheet. Their association with survival and progression-free survival (PFS) was compared using standard tests of significance. P values of <0.05 were considered statistically significant. PMS and OS were calculated for the entire cohort of patients. The survival curves were plotted using the Kaplan–Meier method.


 » Results Top


A cohort of 37 patients who had undergone pulmonary metastasectomy with a potentially curative intent were included and analyzed. The vast majority of our patients were males (n = 28) <19 years (n = 24) with distal femur being the most common site of primary (n = 19). Conventional osteosarcoma (n = 21) was the most common histological subtype followed by chondroblastic variant (n = 11). Seven patients (20%) presented with pathological fracture and underwent upfront surgery. Limb salvage surgery was performed in 73% of the patients for the primary tumor, whereas the rest underwent amputation.

Overall, 35 (97%) patients had completed all the planned chemotherapy prior to pulmonary metastasectomy; however, 23 (77%) had a poor histological response to chemotherapy. (<90% necrosis). In 89% (n = 33) of patients, lung was the only site of metastasis with 54% (n = 20) had single pulmonary metastasis and rest had multiple resectable pulmonary nodules. About 78% (n = 29) had unilateral metastasis, whereas 22% had bilateral. The metastasis was >1 cm in 65%, with pleural involvement seen in only 14% (n = 5) of patients with only 11% (n = 4) having positive margins. Majority of the patients (78%, n = 29) underwent procedure only once, whereas 22% had metastasectomy done twice. About 19% (n = 7) received second-line chemotherapy postmetastasectomy. About 30% of the patients had pulmonary recurrence. The demographic details of our patient cohort are shown in [Table 1], whereas the characteristic of pulmonary metastasis is shown in [Table 2].
Table 1: Patient and primary tumor characteristics

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Table 2: Characteristics of metastases

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The median OS of our patient cohort was 38 ± 2.7 months. [Figure 1]. The 2-, 3-, and 5-year OS were 86 ± 5.8%, 60.8 ± 8.6%, and 20.7 ± 7.4%, respectively. The median post-metastasis survival was 23 ± 5.7 months [Figure 2]. The 2-, 3-, and 5-year postmetastasis survival were 46.7 ± 8.7%, 27.4 ± 8.4%, and 18.8 ± 7.7% respectively. The factors that were found to be significantly influencing OS in our study were completion of systemic chemotherapy, local recurrence, disease-free interval (DFI) of >2 years and absence of pulmonary recurrence postmetastasectomy [Table 3]. The factors significantly influencing postmetastasis survival were completion of all the planned cycles of chemotherapy and pulmonary recurrence.
Figure 1: The median overall survival of our patient cohort was 38 ± 2.7 months. The 2- , 3-, and 5-year OS were 86 ± 5.8%, 60.8 ± 8.6%, and 20.7 ± 7.4% respectively

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Figure 2: The median postmetastasis survival (PMS) of our patient cohort was 23 ± 5.7 months. The 2-, 3-, and 5-year PMS were 46.7 ± 8.7%, 27.4 ± 8.4%, and 18.8 ± 7.7%, respectively

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Table 3: Analysis of factors predicting overall survival (OS) and postmetastasectomy-free survival (PMS) in months

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 » Discussion Top


Pulmonary neoplasms in children and adolescents are more commonly caused by metastatic disease rather than by primary tumors. Contrary to the epithelial cancers, the vast majority of patients with sarcomas metastasize to the lungs.[4] In our patient cohort, in 89% (n = 33) of the patients, lung was the only site of metastasis, 54% (n = 20) of whom had a solitary pulmonary metastasis. The findings are more or less similar to the findings of the Co-operative Osteosarcoma Study Group, which reported that among the patients with metastases at diagnosis, 81% had lung metastases and 62% had lung only metastases.[3]

A computerized tomography (CT) scan of the chest is considered mandatory in the planning of any lung metastasectomy. An FDG-PET-CT scan (fluorodeoxyglucose-labeled positron emission tomography) has the added advantage of ruling out extrathoracic disease. A study by Kayton et al.[5] showed that the CT chest findings tend to underestimate the extent of metastatic disease in up to 35% of the patients with primary osteosarcomas; the authors further interestingly found that approximately one-third of the resected nodules actually turned out to be benign.[5] It is important to note that imaging technology has over the years considerably improved and radiologists are now better equipped to more accurately identify pulmonary metastases in osteosarcomas.[6] Despite this, it is important that thoracic surgeons consenting patients for pulmonary metastasectomy discuss the fact that despite improvements in cross-sectional imaging, not all palpable pulmonary nodules can be detected preoperatively.

The four broad principles of selection of patients for pulmonary metastasectomy have not changed much since its initial description by Thomford in 1965. They include technical resectability, ability to tolerate the general and functional thoracic surgical risk, control of the primary tumor, and the absence of extrathoracic metastasis. In 1991, an International Registry of Lung Metastasis was constituted with a mandate of developing a sound rationale for pulmonary metastasectomy.[7] Although this study contained no control group of nonoperated patients, the significantly better 5-year survival in the group of patients that underwent a R0 resection (36%) compared with incomplete resection group (13%) indicated the oncological benefit of pulmonary metastasectomy. Pulmonary metastasectomy for sarcomas has since then been widely accepted in clinical practice with several more retrospective studies demonstrating an improvement in the survival outcomes.[7],[8] Further, given the young age and performance status of patients with extremity osteosarcomas, addressing the pulmonary metastasis with a curative intent is imperative.

Some authors, however, argue that the evidence from the historical comparisons with patients treated with chemotherapy is not sufficient to make a definitive conclusion that pulmonary metastasectomy improves survival, because the patients who were treated with nonoperative therapy invariably had advanced unresectable disease. This apparent better survival of patients with pulmonary metastasectomy over chemotherapy (due to an inherent selection bias) has made some authors to question the actual benefit of pulmonary metastasectomy.[9],[10] An interesting study by Salah et al.[11] found that pulmonary metastasectomy was associated with an improvement in survival of osteosarcoma patients with resectable metastases. The study demonstrated that osteosarcoma patients with resectable metastases who were managed without pulmonary metastasectomy had more than five times higher risk of progression and more than four times higher risk of death as compared with osteosarcoma patients with resectable metastases who were managed with pulmonary metastasectomy. The survival outcomes of our study were comparable with many of the published case series.[2],[3],[7],[10]

Pulmonary metastasectomy from the technical stand point can be performed by two main approaches, i.e., the open and the minimally invasive approaches. Thoracotomy, median sternotomy, and clamshell incisions are the traditional open approaches for pulmonary metastasectomy. Minimally invasive approach by VATS/robotic surgery allows for faster recovery and lesser pain, as compared with the traditional open approaches. Nonanatomical wedge resection with clear margins is considered as an adequate technique for pulmonary metastasectomy mainly due to its potential for lung parenchymal preservation. This can be easily achieved in pulmonary lesions which are located in the periphery of the lungs, especially when they are fewer in number. However, centrally located lesions that are closer to the hilum often require anatomical resections, such as a lobectomy rather than the more commonly performed wedge resections. More importantly, some authors have found that patients with centrally located pulmonary metastatic disease in osteosarcoma had a very poor prognosis when compared with the peripherally located metastatic lesions, thus further reiterating the critical importance of the actual location of the pulmonary metastatic disease rather than the actual number of lesions.[12]

Some thoracic surgeons believe that manual tumor palpation is a critical intraoperative step in detecting pulmonary metastases, thus advocating an open surgical approach. However, a few other authors have shown that both the approaches, thoracotomy and thoracoscopy, were both feasible options for resection of pulmonary metastasis and have found no statistically significant differences in survival at 1, 3, and 5 years.[13]

The ability to detect additional metastatic lesions intraoperatively is more likely in osteosarcoma, because of the associated osteoid formation. A skilled surgeon can actually palpate lesions down to a size of 1 mm; this becomes important as multiple studies have shown that complete surgical resection of metastatic disease can potentially be curative.[14] Further, among the reports of pulmonary metastasectomy, some skilled and aggressive surgeons have reported very high numbers of metastases resected, i.e., as many as 80–100 nodules during a single thoracotomy. It is noteworthy to state that some of the lesions in the reported series were, in fact, patients who were considered inoperable in other institutions because of presumed extensive or recurrent disease. In fact, the highest number of pulmonary nodules surgically removed has been reported to be around 250, further reiterating the importance of surgical expertise in the performance of aggressive pulmonary metastasectomies.[10]

Despite a complete resection, further pulmonary metastases eventually develop in about 21%–83% of these patients. Many of these patients with pulmonary recurrence can still be salvaged with additional lung resections.[15] Recurrent metastasis may at times represent residual lesions that might have been undetectable at the time of the initial pulmonary metastasectomy.[16] Technically, the decreased ability of patients to tolerate repeated pulmonary surgeries and the inevitable presence of pleural adhesions from the prior metastasectomy can make recurrent pulmonary metastasis hard to perform. A meta-analysis by Li et al.[17] demonstrated that recurrent pulmonary metastasectomy was an effective option for sarcoma patients with recurrent pulmonary disease. Further, it was found that patients with a longer postmetastasectomy DFI and with lesser number of metastases tended to have better OS.[18] A series from the Massachusetts General Hospital, of 97 patients operated on for pulmonary metastases between 2002 and 2008 reported that 69% of 29 patients, who had multiple pulmonary metastasectomies were alive at 5 years as compared with 41% of 60 patients who had a single pulmonary metastasectomy and found the difference to be statistically significant. The authors concluded that repeated pulmonary metastasectomy in carefully selected patients has the potential to improve survival despite recurrent disease.[19] The effectiveness of recurrent pulmonary metastasectomy was further demonstrated in our series as well with 22% of our patients undergoing a second metastasectomy and their median postmetastasis survival was 23 ± 5.7 months. The 2, 3, and 5-year postmetastasis survival of our patient cohort was 46.7 ± 8.7%, 27.4 ± 8.4%, and 18.8 ± 7.7%, respectively.

In an attempt to further improve the performance of pulmonary metastasectomy, certain authors have attempted the use of radiofrequency ablation,[8] laser assistance,[20] targeted near-infrared molecular imaging,[21] and isolated lung perfusion using melphalan at 37°C, with encouraging results.[22]

There is no major consensus about the timing and effect of chemotherapy for lung metastases. Saeter et al.[23] reported that administrating salvage chemotherapy was an independent factor for improved OS in patients with distant metastases. Some studies reported that salvage second-line chemotherapy for patients with unresectable lesions or with incomplete metastasectomy was associated with a longer post relapse-free survival.[24] About 19% of our patients received salvage chemotherapy following metastasectomy. Second-line chemotherapy, in our cohort, was considered in selected patients with metachronous lesions excised with negative margins and with a DFI of >2 years. Patients with unresectable pulmonary metastases have an extremely poor prognosis despite the use of various systemic chemotherapeutic agents. There is, hence, a need to explore alternative therapeutic strategies in this subset of patients.

The prognosis of patients with pulmonary metastasis from extremity osteosarcoma is variable and is dependent on a multitude of factors. A formal analysis of the various prognostic factors that were found to be significantly influencing OS in our study was DFI >2 years, completion of the planned systemic chemotherapy, local recurrence, and absence of pulmonary recurrence postmetastasectomy. Further, the factors significantly influencing postmetastasis survival were completion of all the planned cycles of chemotherapy and pulmonary recurrence [Table 3]. Various other factors, such as age, response to chemotherapy of primary, histology, number, location, laterality, size of metastasis, and margin positivity of metastasectomy specimen, which has been shown to influence either OS[1],[25],[26],[27],[28],[29],[30] or the postmetastasectomy survival outcomes,[18],[19],[31],[32] in many studies did not have a bearing on the outcomes in our study.

There are three retrospective case series on pulmonary metastasectomies from primary osterosarcomas reported from India. The first series had 36 patients, of which only 16 had undergone a pulmonary metastasectomy from an osteosarcoma primary.[33] The number of pulmonary metastasectomies in the other series was only five, although the authors showed a comparable survival despite delaying metastasectomy following the completion of chemotherapy.[34] In a more recent study,[35] 80 treatment-naïve patients of metastatic osteosarcoma were treated with a novel OGS12 protocol, primarily comprising of a dose-dense, non-HDMTX–based sequential doublet regimen. The authors reported a favorable toxicity profile with the novel regimen and more importantly reported survival outcomes comparable with the other published series. Only 28 patients in this series underwent pulmonary metastasectomy. Interestingly, the performance of surgery was seen to be influencing the survival outcomes only on a univariate analysis; the significance was, however, lost on a multivariate analysis. The authors hypothesized that a complex interplay of various factors including tumor biology could have possibly diluted the effect of surgery. The authors finally advocated the use of an aggressive approach of intensive combination chemotherapy, surgery, and pulmonary metastasectomy in a select group of patients of metastatic osteosarcoma.[35]

Some authors have suggested a risk stratification model to aid in better patient selection for pulmonary metastasectomy. The authors identified seven risk factors associated with poor OS, i.e., age >45 years, DFI <1 year, synchronous disease presentation, location/type of sarcoma, thoracotomy, and performance of a lobectomy.[36] In yet another study, five independent prognostic factors that were seen to influence OS was identified. The factors identified included pretreatment platelet count, alkaline phosphatase, neutrophil count apart from tumor size, and the Enneking stage.[37]

A few other authors have explored the role of molecular prognostic factors in pulmonary metastasectomy specimens. A study that included 29 osteosarcoma patients with pulmonary metastases revealed that evaluation of VEGF-A, Ki67, and VEGF-C in the pulmonary metastasectomy specimens effectively predicted survival outcomes in patients following pulmonary metastasectomy.[38]

Given the lack of robust evidence to define clinical practice for patients with pulmonary metastatic disease, there is variability in the reported management of pulmonary nodules in patients with osteosarcoma and this objectively was brought out in a questionnaire-based study.[39] The recommendation from the various consensus guidelines and expert opinion is to completely resect all metastatic disease whenever feasible, in carefully selected patients.

The subset of highly selected patients in clinical practice would generally include patients with lung metastases only, a longer DFI (>1 year) and lesser number of metastatic lesions (single better than multiple). An aggressive surgical approach to achieve a complete surgical resection is vital for better survival outcomes.[40] It also confirms the importance of chemotherapy in patients in whom surgical treatment is not feasible. Although the analysis from COSS study suggested a limited role of chemotherapy even in heavily pretreated patients with multiple recurrences, a recent study showed that chemotherapy could possibly improve survival in patients who had macroscopic disease after metastasectomy and in patients who could not undergo a metastasectomy following a second recurrence.[40]

The major limitations of our study are the modest numbers, heterogeneity in the presenting characteristics of the metastatic disease despite restricting the study to resectable metastasis from extremity osteosarcomas, and the retrospective nature of the study which precludes us from making any firm management recommendations. This has been a limitation of a majority of the published series as well.

However, our study does bring our many important facets with regards to the performance of pulmonary metastasectomy in extremity osteosarcomas. Given the comparable survival outcomes with the other published series, our study reiterates the consideration for pulmonary metastasectomy in selected patients of extremity osteosarcomas. Further, our study suggests that no patient should be denied the option of pulmonary metastasectomy, merely because of the presence of certain isolated risk factors that seem to portend a poorer outcome. Future studies are warranted, particularly in patients with a high-risk profile, so as to better define the need, timing and modality of pulmonary metastasectomy.

In conclusion, our study reiterates the need for consideration of pulmonary metastasectomy in carefully selected patients of extremity osteosarcomas. In routine clinical practice, we recommend that the final decision to proceed with pulmonary metastasectomy should ideally be taken by a multidisciplinary tumor board on a case-by-case basis.

Ethical issues

All procedures performed in this case report were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Appropriate informed consents have been obtained.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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