Progressive Improvement in 5-Year Survival Rates for Extremity Soft Tissue Sarcomas from 1999 to 2019

Background Extremity soft-tissue sarcoma (ESTS) is a group of rare, heterogeneous malignancies. Previous studies have demonstrated a progressive improvement in 5-year survival rate over time, but recent trends are unknown. Therefore, this study aimed to provide an update on the clinical characteristics and 5-year survival rate of ESTS from 1999 to 2019. Methods This retrospective cohort study used the Surveillance, Epidemiology, and End Results (SEER) database. Overall, 5,654 patients over the age of 15 years with primary ESTS diagnosed between 1999 and 2019 were included. Data on patient demographics, clinical characteristics, and survival were extracted. Patients were grouped by year of diagnosis: 1999–2005, 2006–2012, and 2013–2019. Kaplan–Meier and Cox proportional hazards regression analyses were performed. Results ESTS occurred primarily in the lower extremity (76.1%) and was frequently grade III (58.3%), >5 cm in size (69.9%), and without metastasis (77.9%) at diagnosis. Furthermore, there was a significant increase in the proportion of patients over age 60 (p < 0.001) and without metastasis (p < 0.001) over the study period. The 5-year survival rate successively improved, from 47% in 1999–2005, to 61% in 2006–2012, to 78% in 2013–2019. Similarly, in multivariate analysis, the mortality rate progressively declined from a hazard ratio (HR) of 3.4 in 1999–2005 to an HR of 2.1 in 2006–2012, with the 2013–2019 group having the best overall survival (p < 0.001). Age, tumor size, grade, and metastasis were negative prognostic factors for survival; radiation and surgery were positive prognostic factors. Conclusions The 5-year overall survival rate for ESTS progressively improved over the 20-year study period, perhaps due to an increasing proportion of older patients diagnosed with local disease. These findings may also be related to earlier detection or more effective treatment over the study period.


Introduction
Extremity soft tissue sarcoma (ESTS) comprises a group of rare, heterogeneous tumors of mesenchymal origin with a propensity for metastasis [1].Te most common histologic subtypes include undiferentiated pleiomorphic sarcoma, leiomyosarcoma, and liposarcoma [2].Te cornerstone of treatment is limb-preserving wide surgical resection, often coupled with radiation therapy, to reduce local recurrence [3].Te role of chemotherapy remains uncertain given the rarity and histologic variability of ESTS but is typically utilized for large, high-grade tumors or metastatic disease [4].
Several patient and clinical factors have been correlated with ESTS prognosis, including patient age, tumor size, and tumor grade [5][6][7].Previous studies [5][6] have reported a 5-year survival rate of 50% to 56%, with a study by Jacobs et al. [7] demonstrating progressive improvement in survival from 28% to 62% from 1991 to 2010.However, the literature is limited with respect to more recent trends in ESTS survival.Terefore, this study aims to provide an update on the clinical characteristics and 5-year survival rate of ESTS from 1999 to 2019.We hypothesized that there would be stepwise improvement in survival rates over the study period.

Methods
Tis retrospective cohort study utilized the Surveillance, Epidemiology, and End Results (SEER) database, developed by the National Cancer Institute, which contains population-based cancer incidence and survival rates.Patients over the age of 15 diagnosed with primary ESTS from 1999 to 2019 were included.Patients with incomplete clinical data on tumor size, grade, metastasis, or treatment were included in incidence calculations but were excluded from all other analyses.
Patients were grouped by year of diagnosis for com-

Results
Of the 10,524 patients identifed, 5,654 were included in the fnal cohort (Figure 1).Patients were excluded for incomplete data on tumor size (n � 1,136), tumor grade (n � 2,570), metastasis (n � 1,097), or treatment (n � 67).Importantly, the exclusion rate was similar across all three time periods.
In addition, there were substantial changes in patient demographics and clinical characteristics over the study period (Table 1).
For instance, from the earliest to the most recent time period, the proportion of patients ≥60 years of age increased (from 42.9% to 51.9%, p < 0.001), as did the proportion of Hispanic patients (from 14.7% to 18.0%, p � 0.038).Clinically, there was a signifcant increase in the proportion of grade I tumors (from 17.4% to 20.7%, p � 0.023).Additionally, there was a signifcant decrease in the proportion of patients with metastasis (from 28.9% to 13.0%, p < 0.001).
Univariate analyses revealed that several patient and clinical factors were associated with survival in all time periods (Table 2).Older age, larger tumors, higher grade, presence of metastasis, and treatment with chemotherapy were all associated with signifcantly lower 5-year overall survival.Treatment with surgery was signifcantly correlated with improved 5-year overall survival.

Discussion
In this population-based study, the incidence of ESTS increased slightly over the 20-year study period, from 1.6/ 100,000 in 1999 to 1.8/100,000 in 2019.Te clinical picture of ESTS also changed, with a greater proportion of older patients diagnosed lower-grade tumors without metastasis.Likewise, the 5-year overall survival rate for ESTS progressively increased from 47% in the 1999-2005 group to 77% in the 2013-2019 group.Given its bimodal age distribution coupled with the aging population, both the marginal increase in incidence as well as larger proportion of older patients with ESTS is not unexpected [8].Te increase in the proportion of patients with lower-grade tumors at diagnosis may be related to advances in imaging, detection, and histopathologic characterization over the study period [7,9].However, the signifcant decline in the proportion of patients with metastasis, particularly in the most recent 2013 to 2019 period, observed in this study contrasts with the increase reported by Jacobs et al. a decade ago [7].Tis discrepancy may be due to diferences in study design, as patients with incomplete clinical data on metastasis were excluded from the current work but were included in the original study, potentially skewing calculated proportions and subsequent analyses.Furthermore, it is possible that a declining metastasis rate in recent time periods may be refective of improved treatment and perhaps earlier detection [10,11].Finally, there were changes in histologic subtype of ESTS over time, with an increase in the frequency of "not otherwise specifed" and "other" subtypes.Tis fnding is likely related to the discovery of new, rare subtypes of soft tissue sarcomas as well as the reclassifcation of other subtypes (i.e., malignant fbrous histiocytoma to undiferentiated pleiomorphic sarcoma) [12].
Trends in treatment remained relatively constant over the study period, with surgery and radiation used in 93%-96% and 56%-59% of cases, respectively.Both surgery and radiation were independent positive predictors of survival, consistent with prior fndings by Jacobs et al. [7].Tough it is    well established that surgical resection reduces rates of metastasis and improves survival, and that radiation reduces the rates of local recurrence, the efect of radiation on overall survival remains inconclusive [13,14].New radiation techniques have been developed over the study period, including proton beam therapy, and their efects on local disease control and overall survival remain to be seen [15].Finally, chemotherapy use slightly declined (23% to 18%) and was negatively correlated with survival.Signifcant selection bias is present for chemotherapy as its use was largely reserved for the treatment of large, high-grade tumors and metastatic disease in this study.Of note, the SEER database only includes initial treatment course, which may underrepresent the utilization of chemotherapy overall.Te 5-year survival rate for this subset of patients is very poor at 5-15%, and this confounding likely accounts for chemotherapy as a negative prognostic factor [14,16].Interestingly, the proportion of patients treated with surgery declined slightly over the study period.Tis remains a relatively small subset, though this fnding is somewhat counterintuitive in light of the decrease in the percentage of patients presenting with metastatic disease.While these fndings may represent a measured approach of attempted systemic therapy as a primary mode of treatment in patients with metastatic disease, further investigation is warranted for this subpopulation.
Multiple predictors of survival were identifed in multivariate regression, including older age, tumor size, grade, metastasis, surgery, radiation, and chemotherapy.Tese prognostic factors are consistent with those identifed in previous studies [5,7,17].While the multivariable regression does demonstrate that metastasis at presentation is a signifcant predictor of 5-year overall survival, the magnitude of the HR is smaller than we would have predicted.Te prior analysis by Jacobs et al. yielded an HR of 3.3, while the current study suggests an HR of 1.4.Tis may be refective of an improvement in the duration of survival with distant metastases over the study period.Te SEER database limits our ability to further understand the complex relationship between the identifcation of metastasis at presentation, the development of metastasis on surveillance, and how those are impacting and impacted by the various other prognostic factors and treatment modalities.
Tis study has several limitations.Te SEER database lacks clinical data on patient comorbidities; local recurrence rates; and detailed treatment information, including surgical margins, radiation dose/duration, and chemotherapy regimen, precluding analysis of the efects of these factors on survival.Clinical data also remain incomplete for a nontrivial number of patients in each time period, resulting in the exclusion of those patients from our analyses.Although it is possible that patients with incomplete data difered substantially from those with complete data, resulting in overstated survival rates, this is unlikely, as similar absolute and relative trends were noted in prior studies that included patients even with incomplete clinical data.
In summary, this study adds an additional decade's worth of data to prior work by Jacobs et al. and provides an important update on the clinical characteristics and survival rates of ESTS [7].Although our fndings are largely on par with those of the previous study, slight diferences in results are likely attributable to extraction of data from 12 registries rather than the original 18 registries.Also, our inclusion criteria were stricter, as all patients with missing clinical data were excluded.

Conclusions
Te 5-year survival rate for ESTS progressively improved over the 20-year study period, with an increasing proportion of older patients diagnosed with lower-grade tumors without metastasis.Tese fndings may be related to earlier detection or more efective treatment over the study period.

Figure 2 :
Figure 2: Age-adjusted incidence of ESTS in the United States from 1999 to 2019.

Figure 3 :
Figure 3: Kaplan-Meier product-limit curves for survival rate of ESTS from 1999 to 2019.

Table 1 :
Patient demographics and clinical characteristics stratifed by time period.