The chemotherapy and radiation in low-grade myobroblastic sarcoma: is there a role?

Background: Low-grade myobroblastic sarcoma (LGMS) is a rare entity with a predilection in the head and neck. There are still no optimal treatment strategies for LGMS. We aimed to investigate the role of chemotherapy and radiation treatment for LGMS. Survival estimate was performed and prognostic factors were identied. Methods: Based on the Surveillance, Epidemiology, and End Result (SEER) database, LGMS patients diagnosed between 2001 and 2015 were involved in our study. Kaplan-Meier curves and log-rank tests were used to estimate overall survival. Cox proportional hazard regression model was performed to identify prognostic factors. Results: A total of 96 eligible patients with LGMS were included, among which 86 (89.6%) received surgical treatment. Twenty-eight (29.2%) patients received radiation treatment while chemotherapy was offered to 20 (10.4%) patients. The median age was 55.0 years old with 22 cases occurred in head and neck region. The mean OS was 125.2 (95%CI 106.3-144.2) months while 1-, 3-, 5- and 10-year OS rates were 88%, 77%, 70% and 59%, respectively. Age older than 60 years, positive nodal status and no surgical treatment were independent prognostic factors for patients with LGMS. Chemotherapy and radiation were not independent prognostic factors for LGMS. Conclusions: Several prognostic factors for LGMS were revealed in this study. Surgical resection is the main therapy while chemotherapy and radiation showed limited effects on survival improvement. Thus, chemotherapy and/or radiation should not be routinely performed in LGMS.

LGMS was reported to be with local recurrence and with low probability to develop distant metastases [9]. Heart and lung can be the distant metastatic sites [10].
Owing to the rarity of LGMS, the optimal treatment is still unclear. As well as other soft tissue sarcomas (STS), surgical excision with negative margin is the primary modality for LGMS [11]. For patients without clear margin, radiation may be an effective treatment [6]. A previous population-based cohort study, based on 49 LGMS patients from the Surveillance, Epidemiology, and End Results (SEER) database, described the demographic and clinical characteristics of LGMS and investigated prognostic factors [12]. However, since the information of chemotherapy was not available and no patient had radiation as the single treatment, the role of adjuvant treatment was hardly investigated. In another two large cohorts, including 18 and 15 LGMS patients, there were only four and three patients received chemotherapy or radiation [1,13]. Therefore, due to the limited sample size, the role of radiation and chemotherapy in LGMS is still controversial.
Based on the SEER database, the purpose of the present study was to investigate the role of chemotherapy and radiation treatment for LGMS. Survival estimate was performed and prognostic factors were identi ed.

Data source and patient population
We included LGMS patients from the SEER database. The database, named as Incidence -SEER 18 Regs The variables were classi ed as following: age at diagnosis (< 60 and ≥ 60 years), gender (male and female), marital status (married, unmarried and unknown), race (white and nonwhite), insurance recode (insured, uninsured and unknown), tumor grade (grade I-II, grade III-IV and unknown), tumor size (< 4 cm, ≥ 4 cm and unknown), nodal status (negative, positive and unknown), SEER historic stage (localized, regional, distant and unknown), surgery treatment (surgery and no surgery), the treatment of radiation and chemotherapy (yes and no/ unknown). Primary site was classi ed into "Head and neck" or "Nonhead and neck" according to Site recode ICD-O-3/WHO 2008.

Statistical analysis
Quantitative data were described as mean ± standard deviation (SD) and categorical data were presented as the number and percentage (N, %). Overall survival (OS) was de ned from the time of LGMS diagnosis to all causes of death or last known follow-up. Disease-speci c survival (DSS) was de ned from the time of LGMS diagnosis to death from cancer or last known event (death or follow-up). Survival curves were generated using the Kaplan-Meier method while log-rank test was used to determine the signi cance of difference in survival curves. In order to investigate the role of treatment on survival, the treatment of surgery, chemotherapy, radiation and variables with P < 0.05 in the log-rank test were further analyzed in Multivariate Cox proportional hazard regression model. All statistical analyses were performed using SPSS 22.0 (IBM Corporation, Armonk, NY) and all charts on survival were prepared by MedCalc 18.11.3. Two-sided P < 0.05 was considered as statistically signi cant.

Ethics Statement
The SEER database is an open database, and the data released from the SEER database do not require informed patient consent because cancer is a reportable disease in every state of the USA. The present study complied with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Results
Characteristics of the patients A total of 96 patients were diagnosed as LGMS and detailed characteristics were shown in Table 1. In the entire population, there was a slightly female preponderance (53.1% vs 46.9%). The median age was 55.0 years old (interquartile range, 36.5-66.8 years). The majority of cohort were married (52.1%), white race (79.2%) and insured (71.9%). The tumor in seventy-four patients located at non-head and neck region such as extremities, abdomen, pelvis region and thoracic region while other 22 cases located at head and neck region. The percentage of tumor grade at I-II and III-IV was 52.1% and 22.9%, respectively.

Survival Estimate And Prognostic Factors
The mean OS for each variable was listed in Table 1. For the total cohort, the mean OS was 125.2 (95%CI 106.3-144.2) months while 1-, 3-, 5-and 10-year OS rates were 88%, 77%, 70% and 59%, respectively (Fig. 1A). Survival curves for surgery, chemotherapy and radiation were shown in Fig. 1B  As to the DSS, the mean DSS was 152.4 (95%CI 135.9-169.0) months. The 1-, 3-, 5-and 10-year DSS rates were 93%, 85%, 79% and 76%, respectively ( Fig. 2A). The mean DSS for each variable was listed in Table 1. The log-rank test showed that the following factors were signi cantly associated with DSS: age, tumor grade, tumor size, nodal status, SEER stage and chemotherapy. Survival curves for surgery, chemotherapy and radiation were shown in Fig. 2B-D. Except for the unknown SEER stage, the positive nodal status was the only independent prognostic factor for DSS HR 24.90 (95%CI 2.24-276.87). Neither the treatment of surgery nor the treatment of chemotherapy or radiation was the independent prognostic factor for DSS. The results of Multivariate Cox regression analysis for DSS were shown in Table 2.

Role of chemotherapy and radiation for patients treated with surgery
In the whole cohort, 10 cases did not receive surgery, among whom three cases received radiation and two underwent chemotherapy treatment. 148.9) months. One patient had both surgery and chemoradiotherapy treatments. This patient was still alive at the last follow up with 39 months of survival. The distribution of patient's survival outcome was shown according to different treatment strategies in Fig. 3. Survival curves for different treatments were generated in Fig. 4 (P = 0.051).

Discussion
LGMS was classi ed as a distinct type of soft-tissue tumors in the World Health Organization classi cation [6]. The purpose of our study was to estimate LGMS survival based on the United States population and to investigate the role of chemotherapy and radiation treatment. In our study, a total of 96 patients were enrolled and analyzed, among whom 86 received surgical treatment. The median age was 55.0 years old with 22 cases occurred in head and neck region. The mean OS for total cohort was 125.2 (95%CI 106.3-144.2) months while the mean DSS was 152.4 (95%CI 135.9-169.0) months.
Based on the largest population with LGMS, a series of prognostic factors were revealed. Although nodal status was an independent prognostic factor for both OS and DSS in statistical analysis, its clinical value should not be overestimated because there were only three cases with positive nodal status (3.1%). In a previous SEER cohort including LGMS patients from 2001 to 2012, since there was one patient with lymph metastasis, the nodal status was not signi cantly associated with the survival [12]. Age order than 60 years was reported to be signi cantly associated with worse OS and DSS (HR = 11.3, P = 0.01; HR = 15.5, P = 0.02 for OS and DSS, respectively) [12]. In our study, age at diagnosis was further proved to be an independent prognostic factor for OS. Due to the rarity of LGMS, more factors can be found with the accumulation of cases.
Surgical resection with a negative margin is the primary therapy to prevent the local recurrence in soft tissue tumors [14]. Keller et al emphasized the importance of surgery on the long-term survival in two children diagnosed with stage I myo brosarcoma [11]. In our cohort, patients with surgery showed longer OS than those without surgical treatment. No surgery treatment was a poor prognostic factor for OS although it was not an independent prognostic factor for DSS.
There has been no guideline recommending chemotherapy for patients with LGMS and the role of adjuvant chemotherapy still remains unclear [12]. The application of chemotherapy for LGMS was reported in some case reports [5,8,15]. The previous study recommended adjuvant chemotherapy as a potential therapy, particularly when the tumor is di cult to be excised completely. Chemotherapy should also be considered if the tumor showed the invasion to the adjacent tissues, or the evidence of the lymphatic and/or hematological metastasis [16]. Chemotherapy was previously reported in a LGMS patient with signi cant clinical improvement [8]. However, due to the absence of su cient clinical evidence on e ciency and side effects, chemotherapy was not recommended [7]. Previous reports have suggested limited role of chemotherapy on LGMS [11,17]. An 8-year-old girl diagnosed with LGMS received three courses of neoadjuvant chemotherapy and presented a 0.5 cm tumor diameter increase. Finally, the girl underwent surgical treatment and there was no imaging evidence of recurrence at 6 years Declarations Ethics approval and consent to participate Not applicable.
Consent for publication after surgery [11]. In our study, patients without chemotherapy treatment or with unknown information about chemotherapy showed longer survival than those who received chemotherapy. Chemotherapy was not an independent prognostic factor for LGMS patients. The inverse survival outcome may be explained by small sample size of patients with chemotherapy or treatment bias by the oncologist.
A case report suggested that radiation might be a curative treatment for intermediate-grade myo broblastic sarcoma [6]. However, LGMS was thought to be poorly responsive to radiation therapy in the literature [18]. The role of radiation could not be assessed due to the fact that no patient had radiation as a single modality therapy [12]. In our study, 28 patients received radiation treatment while only two of them had single radiation treatment. Radiation was not an independent prognostic factor for LGMS. Besides, in order to access the adjuvant effects of chemotherapy and radiation after/before surgery, we analyzed the survival for patients who underwent surgery. The result showed chemotherapy and radiation therapy had a limited role when added to surgery in the treatment of LGMS.
This work had some limitations. First, some variables were not available in SEER database such as extent of surgical resection, lymph node dissection, margin status, which were reported to be commonly associated with STS patient's survival. Second, previous studies have documented that oral cavity is the preferred location for LGMS [7,17]. However, only four cases occurred in the oral cavity in the present cohort. The difference may attribute to the inaccurate coding within the SEER database [12]. Third, the speci c medical regimen of the adjuvant chemotherapy was not available in SEER database. Thus, we cannot analyze the effect of certain chemotherapy regimens on LGMS.

Conclusions
LGMS is an extremely rare sarcoma with the mean overall survival of 125.2 months. Nodal status was an independent prognostic factor for both OS and DSS while age older than 60 years and no surgical treatment were poor independent prognostic factors for OS. Surgical resection is the primary modality for LGMS while chemotherapy and radiation showed limited effects. The adjuvant application of chemotherapy and/or radiation in LGMS was not correlated with the improved survival, thus, chemotherapy and/or radiation should not be routinely performed in LGMS.