Clinical value of pulmonary metastasectomy for thyroid malignancies: a systematic review and meta-analysis

Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. 1


IntroductIon
Thyroid cancer is the most common endocrine malignancy worldwide, and the reported prevalence of thyroid cancer is increasing. 1,2 While select early stage thyroid cancers may be observed or treated with thyroid lobectomy alone, the standard treatment of thyroid cancer consists of surgical resection with total thyroidectomy sometimes followed by radioactive iodine (RAI), which ablates residual primary tumor and metastases. 3,4 This approach is generally effective, resulting in a no evidence of disease status in most patients and achieving an overall estimated 85%-93% 10-year survival rate in patients with differentiated thyroid malignancies. 4,5 Thyroid cancer tends to invade locoregional lymph nodes and uncommonly invades distant nodes, with estimated rates ranging from 4% to 30%. 2,4,6,7 However, distant metastasis is strongly associated with poor treatment outcomes and reduced long term survival. The majority of distant metastases occur in the chest, with the most common site being the lung. 3,4,5 Radioactive iodine is the first line treatment protocol in patients with pulmonary metastasis; unfortunately, RAI is not always curative, and more than half of patients experience disease progression despite repeated ablations, resulting in a reported 10-year survival rate of 10-18% for RAI treatment in patients with pulmonary metastasis. 8,9,10 Molecular targeted therapy for locally advanced or metastatic iodine-refractory differentiated thyroid cancer (DTC) have been approved; however, while these approaches prolong survival, outcomes are unsatisfactory. 11,12,13 Surgical resection of head and neck and upper mediastinal metastases can prove effective for patients with RAI-resistant disease, but resection of pulmonary metastases is more controversial, despite its having a standard role in the treatment of other malignancies, including sarcomas, germ cell tumors, and other carcinomas. 4,7 Several studies suggest that pulmonary metastasectomy (PA) may be an effective treatment option in RAI refractory pulmonary metastasis. However, there is currently no consensus among practitioners regarding its use, indications, and associated morbidity and mortality in thyroid cancer patients. We therefore aim to systematically analyze the literature examining the role of PM in thyroid cancer to better delineate its clinical value.

Search Strategy
Articles reporting pulmonary metastasectomy in patients with thyroid malignancies were systematically identified using the electronic PubMed, Cochrane, and MEDLINE databases. Keywords used included "pulmonary metastasectomy" (PM), "lung metastasectomy" AND" thyroid cancer" or "thyroid malignancy" or "papillary thyroid cancer" or "follicular thyroid cancer." Only articles published in English were considered for review. One hundred and seventy-four abstracts were reviewed, and 155 of these articles were excluded from further consideration ( Figure 1). All remaining articles (n = 18) were analyzed using selection criteria based on PRISMA guidelines.

Selection criteria
Our inclusion criteria required that the study: 1) describe patients who underwent pulmonary metastasectomy for thyroid cancers, and 2) provide treatment outcomes of pulmonary metastasectomy. We excluded papers if they: 1) only detailed pulmonary metastasectomy for patients who didn't have thyroid malignancy, 2) provided information for fewer than five patients, and 3) did not describe treatment outcomes. All articles remaining after applying exclusion criteria (n = 7) were included in the systematic review and meta-analysis.

Data extraction
From seven retrospective chart reviews, we extracted the following information to include in our database: total number of thyroid cancer patients who underwent PM, mean age at thyroid cancer diagnosis, age range for all patients, type of surgical approach used for PM, number and type of surgical complication, five-year survival rate, sex, average age, laterality of pulmonary metastases, perceived favorable prognostic factors, and primary tumor pathology. Data were then tabulated in Excel and statistical analysis was performed for cumulated data. Demographic variables, treatment outcomes, and complication rates were calculated by using descriptive statistics. Heterogeneity was examined by using Cochrane's Q test and I 2 statistic.

results
Seven studies published between 1998 and 2017 were reviewed. The total number of patients with a thyroid cancer diagnosis who underwent PM was 174. Of the patients whose sex was provided (n = 107), 52.3% were male, 47.7% were female, and the average patient age was 54.8 with a pooled age range of 10-90. Characteristics of the seven studies, including patient age and sex, are reported in Table 1. The most common primary thyroid tumor pathology was papillary (48.0%; n = 73), followed by follicular (37.5%; n = 57), medullary (7.9%; n = 12), Hurthle (5.9%; n = 9), and anaplastic (0.7%, n = 1). The distribution of thyroid cancer histology is summarized in Figure 2. Pulmonary metastases were more frequently reported to be bilateral (n = 57) than unilateral (n = 37), and thoracotomy (n = 68) was more frequently used as the surgical approach to PM than sternotomy (n = 28) or thoracoscopy (n = 14). The overall absolute 5-year survival rate post-PM was 67.7% (average survival rate based on pooled data) with a pooled range of 32.5%-84.0%; one paper did not report the 5-year survival rate. Sampson et al reported a 3-year survival rate of 77%, and Porterfield et al and Moneke et al reported 37.5% and 56% survival rates, respectively, at 10 years post-surgery ( Table 2). Three papers described favorable prognostic factors for patients who underwent PM, with two papers reporting young age (45 years old) at initial cancer diagnosis and papillary histology of the primary tumor (Figure 3a, Figure 3b) as predictors of a favorable outcome. Others included a disease free interval of greater than three years, iodine avidity of the thyroid cancer, thyroglobulin levels of less than 10 ng/mL (Figure 3c), thyroglobulin level reduction of 80% post-metastasectomy, age less than 45 at time of thyroid cancer diagnosis, R0 (negative microscopic margins) metastasectomy, and systematic mediastinal lymphadenectomy.

Clinical Value of Pulmonary Metastasectomy for Thyroid Malignancies: A Systematic Review and Meta-Analysis
Dundar et al.
The most common complications from PM reported in the seven papers were transient atrial fibrillation (total number of patients = 3) and surgical wound infection (total number of patients = 3). However, only 25 out of 174 patients (14.4%) were reported to have complications post-surgery, and only two patients died due to surgical complications. All observed complications are described in Table 3.

dIscussIon
The first-line treatment for thyroid cancer metastasis to the lung is radioactive iodine (RAI), which offers only a 50% survival rate at six months and less than a 20% 10-year survival rate. 5,14 Having RAI refractory PM is considered a poor prognostic factor. In contrast, pulmonary metastases secondary to renal "ND" signifies that the data was not provided by the study.       The advent of effective multitargeted kinase inhibitors for recurrent/metastatic DTC creates another option for patients with PM from iodine refractory thyroid cancer. In particular, the multitargeted kinase inhibitor lenvatinib was approved for iodine-refractory recurrent/metastatic disease on the basis of progression free survival improvements in the phase III SELECT trial greater than had been achieved in other placebo-controlled trials in DTC. 11,12,13 The 65% response rate and improvement in progression free survival from 3.6 months to 18.3 months creates an attractive potential alternative option. None of the studies that we identified compared results with PM versus targeted therapy. Future studies could compare outcomes of either multitargeted kinase inhibitors or combination therapy. Since many patients with metastatic DTC will have prolonged survival, they may benefit from such an aggressive approach.
In 1947 Alexander and Haight suggested the first known selection criteria for PM, which were later revised by Thompson in 1965. These are: 1) the primary tumor must be controlled, 2) no extrathoracic metastases exist, with the exception of hepatic metastases, 3) the metastases are resectable, and 4) the risks of surgery are acceptable. 16,17 Additionally, the International Registry of Lung Metastases lists disease free index, complete resection, and number of nodules as favorable prognostic factors. 18 Although these criteria are used today by surgeons to guide selection of patients for PM, there is no current consensus on favorable prognostic factors for patients with thyroid cancer metastases to the lung specifically. The reviewed literature suggests that younger patients have a lower mortality rate. However, whether older age should be considered a relative contraindication for PM or simply increases disease-specific mortality regardless of treatment modality is unclear. 19 Additionally, although it appears that papillary thyroid carcinoma carries a better prognosis over other thyroid cancer histotypes post-metastasectomy, it is possible that this trend is due to the lower mortality of papillary thyroid carcinoma in general. 20 Thyroglobulin levels of lower than 10 ng/mL and relative decreases of at least 80% have been suggested by Moneke et al to positively correlate with improved survival. 7 Furthermore, they reported that R0 (microscopic negative margins) resection of pulmonary metastases is associated with a significantly increased survival rate versus incomplete resection, and that systematic mediastinal lymphadenectomy also significantly decreases mortality, possibly through improved cancer staging in addition to removal of the metastases. 7 These findings suggest that outcomes can be improved with more complete surgical resection, supporting the role of aggressive treatment in these patients.
Admittedly, this study has several limitations, mainly owing to the small number of papers that met our inclusion criteria. There are few studies that specifically examine the role of pulmonary metastasectomy  Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).
2 in thyroid cancer treatment, and to our knowledge there are no prospective studies that compare morbidity and mortality rates between medical and surgical treatment in these patients. It is therefore difficult to determine precisely the degree to which PM improves survival rate over RAI and other treatment modalities. Additionally, even among the seven papers that met our inclusion criteria there is heterogeneity in the outcomes and patient characteristics measured. Therefore, we can only draw limited conclusions regarding survival rates, surgical complications, and prognostic factors. Future randomized studies should compare PM to other treatment modalities, including RAI alone, to conclusively determine that it provides a statistically and clinically significant benefit and to more completely determine whether it is safe both peri-operatively and long-term. Additional research should seek to define prognostic factors for morbidity and mortality and to identify characteristics of good surgical candidates.
conclusIon This is the first study to systematically review the role of pulmonary metastasectomy in patients with thyroid cancer; the study design was adapted from PRISMA checklist ( Table 4). The data collected in our study demonstrate that PM is associated with superior survival rates to those reported for radioactive iodine treatment alone, with approximately two-thirds of patients surviving at five years' follow-up. Moreover, PM appears to be associated with low morbidity and a very low mortality rate suggesting that it is both a safe and effective option for patients when indicated. Factors that seem to indicate a favorable prognosis after metastasectomy include papillary histology of the primary tumor and young age of the patient at the time of thyroid cancer diagnosis; lower thyroglobulin levels and more aggressive surgical treatment possibly improve outcomes. It is possible that these characteristics may be used to select good surgical candidates. In patients with pulmonary metastases secondary to thyroid cancer, surgical intervention should be considered after radioactive iodine ablation fails in patients without contraindications. We recommend prospective randomized studies be conducted to confirm that a survival benefit for PM over RAI alone exists. Future studies should also try to better characterize indications for surgery and to assess long-term morbidity of PM. Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

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Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

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Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

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Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

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Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

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Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

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Risk of bias in individual studies 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.  n/a

Summary of evidence
24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

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Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

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Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.

FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.