This prospective, observational study was conducted from October 2017 to September 2019 at a tertiary care center in India. In this study, we had planned to include total 100 patients of STS, considering 5% level of significance (?), 7% margin of error (L), taking 1-year mortality of 13%,[7] and assuming 10% drop-outs/attrition/lost to follow-up. Patients aged 18 years and above, with histologically proven STS, were included in the study. Patients with recurrent disease, Ewing?s sarcoma (EWS), gastrointestinal stromal tumors, and sarcomas arising from the bone were excluded from the study.

Baseline assessment included demographical data, clinical history, physical examination, histopathology on core-needle biopsy, or surgical sample. For staging, contrast-enhanced computed tomography (CECT)/magnetic resonance imaging (MRI) for the primary tumor and CECT chest or positron emission tomography (PET)/CT for metastatic workup were done. Histopathological subtyping and grading were done as per the World Health Organization classification and Federation Nationale des Centres de Lutte Contre le Cancer (FNLCC) grading system, respectively.[2] [13] [14] The staging was done as per the American Joint Committee on Cancer eighth edition tumor?node?metastasis staging.[15]

In the case of localized and resectable oligometastatic STS, patients were treated with surgery. Only lung-limited metastases were considered for resection. The local multidisciplinary team determined the resectability of lung metastases after discussion in the tumor board. Perioperative therapy with radiotherapy ? chemotherapy was considered as per the standard guidelines and/or tumor board decision. Chemotherapy in the adjuvant or neoadjuvant setting included doxorubicin 25 mg/m2?for 3 days with ifosfamide 3 g/m2?for 3 days once every 21 days except in rhabdomyosarcoma, in whom vincristine, actinomycin D, and cyclophosphamide were used. In the metastatic setting, depending on the treating physician?s discretion, doxorubicin 25 mg/m2?for 3 days with or without ifosfamide 2 to 3 g/m2?for 3 days once every 21 days was used based on fitness, age, and tumor burden.

In the neoadjuvant setting, response assessment was done after 4 weeks of completion of radiotherapy or after three cycles of chemotherapy. The response assessment was done using the RECIST version 1.1 response criteria.

At the end of therapy, CT/MRI of the primary site and CT chest were done to document disease status. Patients who have achieved remission or stable disease were followed-up once in every 3 months with clinical evaluation. CT/MRI of the primary site and CT chest were done in every 6 months, in the first 2 years, and then annually in surgically treated patients. Patients treated with palliative chemotherapy and those who achieved at least stable disease were followed-up with repeat imaging in every 3 months or at clinical progression. For analysis of results, patients who belonged to stage IA to Stage IIIB were grouped under localized STS cohort and those with lymph-nodal or distant metastases under stage IV or metastatic disease. DFS was defined as the time from the date of biopsy to the time of disease recurrence or death, whichever occurred first. Progression-free survival (PFS) was defined as the time from the date of biopsy to the time of progression or death, whichever occurred first. OS was defined as the time from the date of biopsy to the time of death due to any cause. Data regarding the recurrence/progression of the disease and survival were noted. The study was conducted after due approval from the Institutional ethics committee, Army Hospital (R & R), Delhi Cantt (Institutional Ethical Committee Rge no: 99/2017, Date: October 24, 2017). The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) and with the Helsinki Declaration of 1964, as revised in 2013. All patients provided written informed consent for participating in this study.

Statistical Analysis

Data were analyzed with SPSS software version 25.0, Released 2017, SPSS for Windows, SPSS Inc., Chicago, Illinois, United States. Descriptive statistics were used for defining the study population and baseline disease characteristics. A Chi-square test was used for the analysis of categorical variables in the study. Kaplan?Meier curves were plotted for survival analyses. A log-rank test was used to compare the data in different groups.

Results

A total of 140 patients of histologically proven STS were included in the study. The median age of the patients was 45 years (range: 18?84 years), and 54.3% (n?= 76) were male. The median duration of symptoms before presentation was 5 months (range: 1?18 months). Extremity sarcoma constituted the most common type constituting 54.3%, followed by trunk sarcoma (17.86%), retroperitoneal sarcoma (14.29%), thoracic and abdominal visceral sarcomas (9.29%), and head-and-neck sarcomas (4.29%). The most common presentation was swelling seen in 70% (n?= 99) of the patients; the swelling was painless in 58.5% (n?= 82) and painful in 12.5% (n?= 17) of the patients. Other complaints at presentation were abdominal pain in 15% of the patients and weight loss, constitutional symptoms, dry cough, breathlessness, radiculopathy, and bleeding per vagina, each in <10>n?= 23/35), followed by liver in 25% of the patients (n?= 9/35). Other sites included pleura (8.5%), spine (8.5%), musculoskeletal (5.6%), and brain (2.8%). The most common histopathologic subtypes were undifferentiated pleomorphic STS (22%), followed by leiomyosarcoma (19%) and synovial sarcoma (16%). The baseline demographic and clinical characteristics of the study population are summarized in [Table 1].

Treatment Patterns

Of 105 patients with localized disease, 92 patients had wide local excision, 5 patients required amputation, and, in 8 patients, tumor was not resectable. Among 97 resected patients, 21 patients received neoadjuvant therapy, 58 patients received adjuvant therapy, and 26 patients underwent surgery alone. Of 21 patients receiving neoadjuvant therapy, 10 patients received radiotherapy (preoperative radiotherapy 50 Gy with 2 Gy/# over 25 days) and 8 patients received chemotherapy (doxorubicin 25 mg/m2?for 3 days + ifosfamide 2?3 g/m2?for 3 days in a 3-week cycle). Three patients received both radiotherapy and chemotherapy before surgery. Fifty-eight patients received adjuvant therapy in the form of external beam radiotherapy (n?= 28) or doxorubicin-based chemotherapy (n?= 16) or both (n?= 14). Of the 21 patients receiving neoadjuvant therapy, partial response was seen in 38% (n?= 8/21) of the patients, and the remaining 62% (n?= 13/21) had stable disease. In the neoadjuvant group, 90.5% of the patients (n?= 19/21) had complete resection (R0) as compared with 76.3% of the patients (n?= 58/76) among those who underwent upfront surgery. The relative risk of having incomplete resection in upfront surgery cohort compared with that of postneoadjuvant therapy cohort was 2.37 (95% confidence interval [CI]: 0.59?9.4;?p?= 0.19).

Among 35 metastatic STS patients, 31 patients received chemotherapy; majority (65.7%,?n?= 23/35) received it as palliative therapy and 39.7% (n?= 8/35) of the patients were treated with curative intent (with surgery + chemotherapy [doxorubicin 25 mg/m2?for 3 days + ifosfamide 2?3 g/m2?for 3 days in a 3-week cycle]) in adjuvant setting, following resection of both primary tumor and metastases. Of 23 patients receiving palliative chemotherapy, partial response was seen in 39.1% (n?= 9/23) and stable disease in 30.4% (n?= 7/23) of the patients; disease progression was reported in 21.8% (n?= 7/23) of the patients.

Survival Outcomes

Among localized STS patients, 36 patients had a recurrence or progressive disease. These were 16 local recurrences and 18 distant metastases. And also, six deaths (5.7%,?n?= 6/105) had occurred in localized STS patients. In metastatic STS patients, there were 14 (40%,?n?= 14/35) deaths and 23 (65.7%,?n?= 23/35) patients had disease progression.

After the median follow-up of 14 months (1?25 months), the 1-year PFS and OS rates were 75.8 ? 3.1 and 87.4 ? 3.1%, respectively. For localized STS patients, the median DFS was 20.93 months (95% CI: 18.09?23.77); 1-year DFS and OS rates were 87.6 ? 3.5 and 95.3 ? 2.3%, respectively. For metastatic STS patients, the median PFS and OS were 9.83 months (95% CI: 4.8?14.85) and 23.90 months (95% CI: 7.43?40.36), respectively. One-year PFS and OS rates were 36.53 ? 9.8 and 61.97 ? 9.1%, respectively (?[Fig. 1]?).

|?Fig. 1?Kaplan?Meier estimate of progression-free survival (A) and overall survival (B) between localized soft tissue sarcoma (stage I?stage IIIB) and metastatic soft tissue sarcoma (stage IV). CI, confidence interval; PFS, progression-free survival; OS, overall survival; SE, standard error.|

In stage-IV STS patients (n?= 35) and those who had curative-intent/definitive therapy (n?= 8), the median PFS was 20.43 months (95% CI: 5.83?35.02) as compared with 6.83 months (95% CI: 4.92?8.74) in those in palliative therapy cohort (n?= 27). The median OS was not reached in the curative intent therapy cohort, whereas it was 12.66 months (95% CI: 9.28?16.04) in the palliative therapy cohort, as shown in [Figs. 2A] and [B].

|?Fig. 2?Kaplan?Meier estimate of progression-free survival (A) and overall survival (B) among metastatic soft tissue sarcoma patients by type of therapy. CI, confidence interval; NP, not reported; PFS, progression-free survival; OS, overall survival, Mo, months.|

Discussion

STSs are a rare and heterogeneous group of malignant tumors arising from the mesenchymal tissue. As per cancer statistics in the United States, the incidence of STSs is approximately 0.72%,[1] whereas incidence data on STSs in India are unknown as studies in published literature are limited to the retrospective institutional case series.[9] [10] [11] [12]

STS incidence increases with age, with the reported median age in Western literature falling in the sixth decade.[16] [17] [18] In our study, the median age was 45 years, which was comparable to that of other studies from different parts of India, as shown in [Table 2]. The median age in the Indian subcontinent is a decade earlier than that in the developed countries. This early occurrence may be due to differing age spectrums of the population in developed countries and India, as a significant proportion of the Indian population is young. A slight male preponderance with a male-to-female ratio of 1.4:1 is reported similar to other studies.[22]

Strengths and Limitations

Our study being prospectively conducted helps to understand the spectrum of STS patients managed at a tertiary care center. It highlights the difficulties in accurate histological subtyping in a real-world setting. It acts as a stepping stone for further studies in a neoadjuvant setting and oligometastatic STS. The limitations of this study include the retrospective design, single-center study nature, and small sample size with a short follow-up; randomized trials with long-term follow-up are needed to delineate differences in the outcomes better.

Conclusion

The median age of STS patients is a decade earlier than that in developed countries. Undifferentiated pleomorphic STS was the most frequent histological type. The median OS was not reached for localized STS patients, with 1-year OS rate being 95.3 ? 2.3%. The median OS for metastatic STS patients was 23.90 months (95% CI: 7.43?40.36). Among metastatic STS, the median OS was not reached for those who underwent curative resection versus 12.66 months (95% CI: 9.28?16.04) for those who received systemic therapy alone. STS requires a dedicated multidisciplinary team for appropriate management. To advance sarcoma care and research in India, multiple institutes should cooperate and form the Indian sarcoma network group.

Conflicts of Interest

There are no conflicts of interest to declare.

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