|Year : 2018 | Volume
| Issue : 9 | Page : 457-462
Clinical efficiency of repeated pulmonary metastasectomy in sarcoma patients with recurrent pulmonary metastasis: A meta-analysis
Yongjiang Li1, Wenbiao Zhang2, Shuangjiang Li2, Chongqi Tu1
1 Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
2 Cancer Center, West China Hospital, Sichuan University, Chengdu, China
|Date of Web Publication||29-Jun-2018|
Department of Orthopedics, West China Hospital, Sichuan University, Guoxuexiang No. 37, Chengdu
Source of Support: None, Conflict of Interest: None
Introduction: Recurrent pulmonary metastasis is common in sarcoma patients following the first pulmonary metastasectomy. Repeated pulmonary metastasectomy (RPM) may be a possible treatment method, but it has several unfavorable aspects. The clinical efficiency of RPM has not been established, as previous studies have reached inconsistent results.
Materials and Methods: Comprehensively literature searches were conducted in PubMed, Web of Science, Embase, and Cochrane Library. All eligible articles were included according to inclusion criteria. Then, a meta-analysis was conducted to clarify the clinical efficiency of RPM.
Results: A total of 9 articles with 464 patients were included. We found that sarcoma patients with recurrent pulmonary metastasis that underwent RPM had significantly better overall survival (hazard ratio = 0.59; 95% confidence interval, 0.44–0.81; P = 0.001). No significant publication bias was found. Sensitivity analysis showed the results were stable.
Conclusion: Selected sarcoma patients with recurrent pulmonary metastasis following the first pulmonary metastasectomy could still benefit from RPM, despite its unfavorable aspects.
Keywords: Meta-analysis, pulmonary metastasis, repeated pulmonary metastasectomy, sarcoma
|How to cite this article:|
Li Y, Zhang W, Li S, Tu C. Clinical efficiency of repeated pulmonary metastasectomy in sarcoma patients with recurrent pulmonary metastasis: A meta-analysis. J Can Res Ther 2018;14, Suppl S2:457-62
|How to cite this URL:|
Li Y, Zhang W, Li S, Tu C. Clinical efficiency of repeated pulmonary metastasectomy in sarcoma patients with recurrent pulmonary metastasis: A meta-analysis. J Can Res Ther [serial online] 2018 [cited 2019 Jul 22];14:457-62. Available from: http://www.cancerjournal.net/text.asp?2018/14/9/457/183207
| > Introduction|| |
Pulmonary neoplasms in children and adolescents were most commonly caused by metastatic disease. The role of pulmonary metastasectomy for metastatic nodules has been deeply studied, with much of the focus on sarcomas. Different from epithelial cancers, 50–60% of patients with sarcomas replace only in lungs, which makes pulmonary metastasectomy a feasible option for treatment. It has been proved that the first pulmonary metastasectomy can increase 5-year overall survival of sarcoma patients with pulmonary metastasis from 15% to about 55%., Therefore, it becomes the standard treatment method for these patients.
However, recurrent pulmonary metastasis is common, which occurred in 45–83% of patients even after complete resection for the initial metastasis., Recurrent metastasis may represent residual lesions that were undetectable at the time of the initial metastasectomy. More importantly, it may indicate the presence of occult micrometastases that disseminate in the remaining lungs this time, which suggests a high possibility of re-recurrence even if a repeated pulmonary metastasectomy (RPM) was performed. Besides, the decreased ability of patients to tolerate a repeated operation and possible pleural adhesions from the previous metastasectomy can make RPM hard to perform. Thus, whether these patients could benefit from RPM is hard to tell. Several studies ,,,,,,,, searched the role of re-exploration with repeated metastasectomy for these patients, but conflict results were reached. The small number of patients included may be a major limitation.
Therefore, we conducted the current meta-analysis to combine published articles and to comprehensively evaluate whether RPM can improve survival outcomes of sarcoma patients with recurrent pulmonary metastasis.
| > Materials and Methods|| |
Comprehensive literature searches were conducted in PubMed, Web of Science, Embase, and Cochrane Library with no restriction to language and publication date. The latest search was conducted on May 8, 2015. The combination of following keywords was used as search terms: “pulmonary/lung metastasis,” “pulmonary/lung metastasectomy,” “sarcoma,” “osteosarcoma,” “chondrosarcoma,” “survival.” Besides, a reference list of relevant publications was traced through Google Scholar for potential studies.
Studies were included in the meta-analysis if they met the following criteria: (1) included sarcoma patients with recurrent pulmonary metastasis after the first pulmonary metastasectomy; (2) the included patients were free of other organ metastases and with a controlled primary site at the time when the metastases were identified; (3) provided survival outcomes or Kaplan–Meier curves of these patients with or without undergoing RPM; (4) were in language of English or Chinese. If the same patient population was reported in more than one article, we selected the latest published article with more patients included. The studies were independently evaluated for eligibility by two authors. Any disagreement was discussed and adjudicated by the corresponding author.
Data extraction and quality assessment
Data of interest were extracted independently by two authors. The required data included: (1) basic information of each article including first author, year of publication, study period, follow-up duration, and study design; (2) data of patient and tumor including patient source, total number of patient, number of patient undergoing RPM, mean age, and histological type of tumor; (3) outcome measures including overall survival, Kaplan–Meier curves and hazard ratio (HR) value.
Each included study's quality was assessed using Newcastle–Ottawa Scale (NOS). Based on the quality of selection, comparability and exposure, a score with a maximum of 9 points was appointed. Articles with 6 or more of the NOS score were considered as high quality and were included in the current meta-analysis.
To evaluate the clinical efficiency of RPM, we calculated the pooled HR with its corresponding 95% confidence interval (CI) as an outcome measure. If the HRs were given explicitly in the articles, we used the original data. If the data were not given explicitly, we calculated the HRs with 95% CIs from Kaplan–Meier curves or available data through methods reported by Tierney et al.
Heterogeneity was assessed using Chi-squared test and I2 statistic. If P > 0.05 and I2 < 60%, the heterogeneity was not considered as significant, and a fixed-effect model was used. Otherwise, a random-effect model was used. Publication bias was evaluated by Begg's test and Egger's test. If P > 0.05 and the funnel plot was visually symmetry, the publication bias was not significant. Besides, sensitivity analysis was conducted to assess the stability of the results by omitting individual study sequentially. All statistical analyses were conducted using STATA version 12.0 (Stata Corp., College Station, TX, USA).
| > Results|| |
Search results and study characteristics
A total of 1074 articles were identified in the initial searches after duplicated removed. After initial screening for title and abstracts, 1049 articles were excluded because they did not meet our inclusion criteria. Then, in the full-text viewing process, 16 articles were excluded. Particularly, we identified two articles reported the same patient population, and we excluded the article  with fewer patients after discussion. Eventually, after full-text viewing, a total of 9 articles ,,,,,,,, published from 2007 to 2013 were included in the current meta-analysis [Figure 1]. The NOS scores of the included articles are counted and shown in [Table 1]. All the studies have 6 or more of the NOS scores.
Baseline characteristics of included articles are tabulated and shown in [Table 1]. All included articles were in English. One study was multicenter designed, and the remaining 8 studies were single-center designed. In total, 464 sarcoma patients with recurrent pulmonary metastases were included, including 176 patients undergoing RPM.
Meta-analysis of the clinical efficiency of repeated pulmonary metastasectomy
The heterogeneity was not significant among the included 9 articles (I2 = 1.8%, P = 0.419). Therefore, a fixed-effect model was used. The analysis showed that sarcoma patients with recurrent pulmonary metastasis that underwent RPM had significantly better overall survival (HR = 0.59; 95% CI, 0.44–0.81; P = 0.001) [Figure 2].
|Figure 2: Meta-analysis of the effect of repeated pulmonary metastasectomy on overall survival|
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Begg's test did not found any publication bias among the included studies (P = 0.348), and visual evaluation of the Begg's funnel plot did not found apparent asymmetry [Figure 3]. No significant publication bias was found according to Egger's test (P = 0.306).
|Figure 3: Begg's funnel plot on publication bias of the effect of repeated pulmonary metastasectomy on overall survival|
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By omitting a single study at a time, the effect of the study on overall estimate could be investigated. The omitting of any study in the analysis made no significant changes in the overall results [Figure 4], suggesting that the results of the current meta-analysis were statistically stable and reliable.
|Figure 4: Sensitivity analysis of the effect of repeated pulmonary metastasectomy on overall survival|
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| > Discussion|| |
Apart from lung cancer resection, pulmonary metastasectomy is the most common operation in the department of thoracic surgery, which represents 15–40% of all surgeries., Performing metastasectomy for sarcoma patients is frequent, for sarcoma metastasizes preferentially to lungs., In 1997, Pastorino et al. published a study including 5206 pulmonary metastasectomies, of which 2173 cases were sarcoma patients. In addition, a study  from the Cooperative Osteosarcoma Study Group found that, among the patients with metastases at diagnosis, 81% had lung metastases and 62% had only lung metastases.
The role of the first pulmonary metastasectomy for sarcoma patients was deeply studied, and it was proved that the first metastasectomy could improve the quality of life and significantly increase the rate of overall survival., Therefore, the first metastasectomy was routinely considered for these patients. However, even after complete resection for initial metastasis, 45–83% patients would develop recurrent pulmonary metastasis,, and the remaining lung was the most common recurrence site. Performing RPM was a possible treatment method, but it may be not as effective as the first metastasectomy for the following possible reasons.
First, recurrent pulmonary metastatic nodules after complete resection of initial metastases represent residual lesions that were hard to be detected by computed tomography or manual palpation at the first pulmonary metastasectomy. This indicates that the metastatic lesions in these patients may be unable to be completely resected through the way of operation. Besides, the recurrence may suggest the presence of undetectable micrometastases that disseminated in the residual lungs during the period after the previous surgery, which means an increased rate of re-recurrence. Second, possible pleural adhesions from the previous operation can make RPM harder to perform and decrease the possibility of a complete resection. Finally, because of limited residual lung capacity, patients are less able to tolerate RPM, which may increase postoperative mortality. Therefore, surgeons are usually reluctant to perform RPM, and thus, its clinical efficiency has not been reached a consensus.
In the current meta-analysis, a total of 464 sarcoma patients with recurrent pulmonary metastasis were included. The patients included in the current analysis were free of other organ metastasis and with a control of primary site at the time when the metastases were detected, which may contribute to a balanced baseline between RPM group and nonsurgical group. We found that patients with RPM had significantly better overall survival compared with those that did not undergo RPM. Besides, the heterogeneity and publication bias was not significant. The sensitivity analysis showed that the results were statistically stable and reliable. Therefore, the analysis suggests that despite its unfavorable aspects, sarcoma patients with recurrent pulmonary metastasis can still benefit from RPM. To our knowledge, it is the 1st time to systematically evaluate the clinical efficiency of RPM in sarcoma patients with recurrent pulmonary metastasis.
In the meta-analysis, only the overall survival was assessed as an outcome measure, the disease-free survival was not evaluated. This is because the included studies did not provide detailed information about disease-free survival. Actually, because of the severity of the disease, disease-free is hard to achieve or cannot maintain for a relatively long period after RPM. The aim of these studies was to identify which group of patients can survive longer, and thus, disease-free survival was not considered as an outcome measure.
Another aspect that needed to be mentioned is that patients were highly selected for RPM in the included studies. The selection criteria were similar, which contained: No evidence of extrapulmonary lesions including local recurrence and other site metastasis; a high possibility of complete resection of pulmonary metastasis; sufficient pulmonary function reserve for the RPM; and other general physical conditions fit for thoracic surgery. Thus, the favorable outcomes for patients in the RPM group may be potentially influenced by the better baseline health condition of the RPM group. Although the significant correlation was still found in a study applying multivariate analysis method, which could reduce bias from some major confounding variables, the results of the current meta-analysis should still be interpreted with caution. The direct evidence of the meta-analysis was that, under strict selection criteria, patients with RPM could significantly prolong overall survival compared with those without undergoing RPM. Future prospective studies are needed to clarify whether RPM was an independent prognostic factor for favorable outcomes in recurrent pulmonary metastatic patients.
Particularly, osteosarcoma (OS) usually has multiple pulmonary metastases, and it remained a reluctant histology subtype for surgeons to perform RPM. Although Dear et al. indicated that a relatively high number of pulmonary metastases is generally not a contraindication for RPM if the metastases can be technically resected, the characteristics of simultaneous multiple metastases of OS could notably reduce the resection possibility. Thus, the effect of RPM could be limited in patients with this particular sarcoma.
The survival outcomes after RPM varied among patients. On the one hand, long-time disease-free survival was hard to archive in these patients from a statistical standpoint. Majority of the patients after RPM would recur in the lungs or other sites if follow-up duration was relative long. On the other hand, isolated patients with long-time survival were reported in the studies. Stanelle et al. reported a patient who achieved long-time survival of 9.4 years, and still alive at the end of follow-up. Similarly, Chen et al. reported a patient surviving 19 years after the first RPM and more than 14 years after the last metastasectomy. The diversity in survival outcomes revealed the different responses of tumor biological behavior to RPM. Pathological research of these tissue samples at different treatment periods may be a promising way for future studies to investigate the changes of the invasiveness of sarcoma cells.
With the increase times of metastasectomy, the pulmonary function sacrificed. The changes in pulmonary function against the surgery times may be a major concern for surgeons to determine following treatment methods. Denbo et al. found that sarcoma children with pulmonary metastasectomies had abnormal long-term pulmonary functions, but the reduction in lung volume and diffusion ability was relative mild. Patients with 2 metastasectomies usually had a 70–90% of total lung capacity reserved, and patients with 5–6 metastasectomies usually had a 50–70% of total lung capacity reserved. Similarly, Petrella et al. found that the pulmonary function loss after three nonanatomical resections was similar to those after one lobectomy. Thus, from the current evidence, it seems that the number of metastasectomies may be not life-threatening if the metastases were resectable and the number of surgery was limited.
However, as the metastasectomies would inevitably lead to the loss of lung function, even if the loss was not life-threatening, it may lead to complications such as decreased exercise tolerance and postactivity dyspnea, thus leading to decrease in quality of life. There was a previous study analyzing midterm changes in quality of life after the first metastasectomy and found significant deteriorations in the items of physical functioning, role functioning, fatigue, pain, and dyspnea, whereas the changes in emotional, cognitive, and social functioning were not found to be significant. However, the changes in the quality of life after RPM were not available in the included studies and also have not been analyzed in literature. Future prospective studies evaluating RPM in sarcoma patients are needed to assess the changes in the quality of life.
Finally, it needed to be mentioned that patients with asymptomatic metastasis may be a special clinic situation. The included studies did not distinguish symptomatic patients from asymptomatic patients. To our knowledge, the benefit was still not clear for asymptomatic pulmonary metastatic patients to perform metastasectomy.,, The benefit of the surgery in asymptomatic patients was less than that in symptomatic patients, and the harms of the surgery would become evident if the benefit was limited. Therefore, the RPM may be only recommended in symptomatic patients, and asymptomatic metastases should be observed.
Overall, the performance of RPM is a cost-benefit option for sarcoma patients with recurrent pulmonary metastases. On the basis of expected sufficient pulmonary function reserve, no evidence of other sites lesion and a high possibility of complete resection, RPM was recommended to perform in symptomatic patients. Besides, some prognostic factors could also assist in identifying patients who are more likely to benefit from the RPM, thus increasing the benefit-cost ratio of the surgery. Patients with a longer postmetastasectomy disease-free interval were found to have better survival, may be partly due to the less aggressive bio-behavior of the tumor cells. In addition, patients with less number of metastases also trended to survive longer after the metastasectomy. More aggressive approaches may be preferred in these patients to maximizing the profit potential of RPM.
Some limitations may exist in the current meta-analysis. First, the patients were highly selected for RPM as mentioned above. Second, histological type of sarcoma differed among the included studies [Table 1]. One studies searched OS, five studies searched soft tissue sarcoma and three studies included patients with mixed types of sarcoma. The nonuniformity may potentially increase the heterogeneity in the meta-analysis. Third, the quality of life post-RPM could not be evaluated in the meta-analysis and should be assessed in future studies addressing this issue. Therefore, the results of the current meta-analysis should be cautiously interpreted despite providing the best available evidence to date.
| > Conclusion|| |
Selected sarcoma patients with recurrent pulmonary metastasis following the first pulmonary metastasectomy could still benefit from RPM, despite its unfavorable aspects.
The authors gratefully acknowledge the staff in the Department of Orthopedics, Department of Thoracic Surgery, Lung Cancer Center and Evidence-Based Medicine Center, West China Hospital, Sichuan University.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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