Long-term Outcomes for Extraskeletal Myxoid Chondrosarcoma: A SEER Database Analysis

Discussion and Conclusions

EMCS is a rare tumor with relatively few studies to guide treatment recommendations and care discussions. We used a large database to establish treatment patterns and outcomes for EMCS patients. These data represent the largest report of EMCS patients with long-term follow-up to date.

Prior reports have demonstrated variable local control rates, but high rates of distant metastasis (6–8, 18). Limitations of the SEER database precluded direct assessment of local control. However, surgery significantly correlated with OS in both univariable and multivariable analysis, suggesting that adequate local control is critical for long-term survival. In our analyses, surgery's beneficial impact was only detected in the sensitivity analysis using MI. This was probably due to the exclusion from our primary complete case analyses of those with missing data. While this is a standard approach to missing data in regression analysis, only 7 of 22 LRD patients who did not receive surgical treatment were available for the complete case analysis.

Because of the apparent importance of tumor grade and size in OS outcomes and also the significant number of cases excluded from the primary analyses, sensitivity analyses were conducted in which the adjusted analyses were repeated using MI to address missing data. For tumor size, the missing data were modest (12.8%). Missing data were higher for tumor grade (46.5%). Over half of cases (51%) were missing at least one of these values, meaning that over half of the initial cases would not be included in a complete case analysis. MI provides an approach to systematically replace the missing data with plausible values, allowing regression analyses to be conducted using the entire case set (15–17). This improves the precision of parameter estimates by allowing the use of a large amount of data that would otherwise be discarded.

As the mechanism for missing data is important in the application of MI, we explored this through correlation between the presence of a missing value in one of the variables and the various other variables used in the analysis. Missing values in tumor grade and tumor size correlated with each another, suggesting a common mechanism. Surgical treatment of disease was negatively correlated with missing data in these two variables. This is not surprising; surgical treatment of a tumor should generally yield information reflecting these pathologic parameters. Missing tumor grade or size did not correlate with any other pretreatment or treatment (chemotherapy, radiotherapy) variable. We posit a missing at random mechanism for the missing data, consistent with use of MI.

There is some disagreement regarding the number of individual dataset imputations that must be undertaken to provide reliable analytic results (16, 17). We undertook 50 imputations, consistent with the recommendations outlined in White and colleagues (17). Other workers indicate that as few as 5 imputations can be sufficient. We found no material differences in the analyses conducted using 50 versus 5 imputations (Supplementary Table S4).

In both complete case and MI analyses, patient age and tumor size were significant. Tumor grade was significant in the complete case analyses but did not remain significant in the MI analyses. From the perspective of treatment, chemotherapy was an adverse prognostic factor in patients treated with surgery for LRD, suggesting selection of patients with an adverse prognosis for its receipt. Among all patients with LRD, chemotherapy treatment was associated with adverse outcomes only when the analysis was conducted using MI. It is possible that the cases with missing data in grade and size disproportionately included those who did not undergo surgery, and therefore received palliative chemotherapy.

While the number of cases requiring imputation of tumor size (12.8%) is within the capability of this approach, imputation of tumor grade, missing in about 46.5% of cases, falls toward the upper end of proportions reliably imputable by this technique. As such, MI data served as a sensitivity analysis, rather than the primary analysis. We urge caution in interpretation of the results based on MI, but feel they still have value in this analysis. Our analyses suggest that, among pre-treatment variables, age, primary tumor size, and possibly tumor grade should be considered for stratification purposes.

A prior study of the SEER EMCS cases suggested benefit for radiotherapy, although there was no statistical improvement in OS with inclusion of radiation (19). Bishop and colleagues report a population in which multimodality therapy with radiation and surgery improved local control over surgery alone (8). Although there was no benefit seen with chemotherapy or radiotherapy in those who had surgery for LRD, limitations of the SEER database preclude our drawing conclusions on potential benefits of these modalities (12, 20, 21). The SEER database contains a heterogeneous population; patients with LRD who received radiation or chemotherapy may have had more aggressive disease biology or may have been more likely to have positive surgical margins and thus a higher risk of recurrence, accounting for the worse outcomes found in our study. Multimodal therapy with surgery and radiation is our institutional practice for EMCS patients presenting with large tumors or those for whom adequate surgical margins cannot be obtained with acceptable morbidity.

Sarcoma pathology is a highly specialized area and change in diagnosis can be seen in a significant proportion of samples after expert second opinion (22). Pathology results in the SEER database are not subject to central review. Thus, diagnostic confirmation depends on the participating institutional pathology review. The presence of the characteristic NRA4A3 fusions could not be confirmed in this dataset. It is possible that some cases may have been misclassified in the registry. Margin status of the resections, likely an important indicator of surgical quality, is also unavailable.

Interestingly, we identify a subset of patients (15% of this study population) who present with metastatic disease and have poor outcomes on par with those of other soft tissue sarcoma subtypes (23). This differs from the general consensus and previous reports characterizing EMCS as an indolent disease (24). Other reports focus primarily on cases with LRD and may therefore underreport this small population with aggressive underlying biology. Improved therapies for this population are sorely needed. The genomic landscape of this subset of patients has not been differentiated from that of EMCS patients as a whole and may reveal underlying factors to explain the more aggressive biology. Additional study is needed to identify whether underlying biological differences or perhaps differing factors in the microenvironment caused this observed difference in metastatic potential. As we found in our multivariate analysis, another possibility is that tumor size and grade are the only significant clinical factors associated with metastasis at presentation.

One of our objectives in this study was to generate benchmarks to be used for future studies. Typical benchmarks for early phase studies, such as objective response rate, local and distant relapse-free survival, and progression-free survival are not available in SEER. OS remains the “gold standard” for oncology study outcomes and is an endpoint available in SEER. We have generated estimated OS outcomes at various time points after diagnosis, along with 95% CI to aid future workers in the design and power calculations for clinical trials (Table 2).

We have included data for the two most common scenarios: those with LRD to be treated surgically, as a benchmark for studies of perioperative therapy, and those with distant disease at diagnosis, representing benchmarks for studies of treatment of advanced unresectable and metastatic disease. Our analyses suggest that age, tumor grade, and tumor size are potentially important stratification factors and covariates to include in adjusted models analyzing the results of clinical trials in the population with surgically treated LRD.

Cytotoxic chemotherapy has minimal activity in metastatic EMCS (25). Targeted agents such as sunitinib and pazopanib have recently demonstrated encouraging results (10, 11). Mechanistic studies of the causative fusion protein have implicated genes involved in axon guidance, neurogenesis, and angiogenesis as potential targets for future clinical development (26). Our data identifies a subpopulation of EMCS patients for whom local control alone is insufficient and improved systemic regimens are sorely needed. Metastatic EMCS carries an overall poor long-term prognosis and patients should be counseled accordingly.