Sarcomas are a rare and heterogeneous group of malignant tumors of mesenchymal origin, which account for <1% of all adult cancers and ~21% of all pediatric cancers worldwide (1). There are >100 histological subtypes of sarcoma, most of which can occur at any age and are not limited to any specific part of the body. Soft tissue sarcomas often form in the muscles, nerves, fat, deep skin tissues and blood vessels (1), and the most common metastatic site is the lungs via the vasculature (1). The most common subtypes are liposarcoma, leiomyosarcoma, chondrosarcoma, osteosarcoma, pleomorphic and synovial sarcoma (2).

Similar to most other types of cancer, surgery is the primary treatment for patients with sarcoma (3). In metastatic disease, long-term disease-free survival and cure can be achieved by performing metastasectomy in selected patient groups, particularly those who have isolated lung metastasis (2). However, for most patients with metastatic soft tissue sarcoma, the goal of systemic therapy is to reduce the tumor burden, relieve symptoms, improve the quality of life and prolong survival (4). Targeted therapies have become increasingly important in recent years due to the limited response obtained with classical cytotoxic agents. Tyrosine kinase inhibitors, such as pazopanib and regorafenib, trabectidin and anti PDL-1 agents have been used to treat soft tissue sarcoma (4).

Pazopanib was the first tyrosine kinase inhibitor used to treat metastatic soft tissue sarcoma (5). It is generally preferred as salvage therapy for patients who progress after standard cytotoxic therapy (4). Considering that most patients eventually succumb to the disease, the main purpose of pazopanib treatment is to prolong their life expectancy (6). Therefore, progression-free survival and clinical response were considered to be the most important criteria of treatment success in the present study. The parameters predicted to affect these data were histological subtype, number of metastatic sites, line of pazopanib therapy and tumor grade. The aim of the present study was to evaluate the progression-free survival time and clinical response of patients with metastatic soft tissue sarcoma receiving pazopanib therapy, and to determine factors that may affect these data, such as histological subtype, number of metastatic sites, line of drug used, age, sex and tolerance to treatment side effects.

In the present study, the median overall survival time was 46 months. The overall survival time was the time from detection of metastasis to death. A previous prospective study had a period of 24 months for overall survival in 212 patients diagnosed with soft tissue sarcoma at the University of Mannheim (Germany) (7). The overall survival time may have been markedly longer in the present study compared with this previous study because most patients that received pazopanib therapy were in the later stages of disease; therefore, patients who died in the earlier stages without receiving this therapy were not included in the present study.

The median progression-free survival time in the entire study cohort was 5 months, which is consistent with the literature. In the sub-analysis of two clinical studies organized by the European Organization for Research and Treatment of Cancer (EORCT), median progression-free survival time was found to be 4.4 months in the patients with metastatic soft tissue sarcoma that received pazopanib therapy (8).

No statistical significance was found in the analysis based on histological subtypes for progression-free survival. This is considered to be due to the large differences in the number of patients between the groups. The synovial sarcoma, leiomyosarcoma and pleomorphic sarcoma groups included a total of 51 patients, the median progression-free survival times were found to be 5, 4 and 4 months, respectively, and the clinical response rates were close to each other. The histological subtype did not affect the success of treatment in these three groups, in which pazopanib treatment was administered most frequently.

The median progression-free survival time was 1.5 months in patients with malignant peripheral nerve sheath tumors and 2 months in patients with fibrosarcoma. Notably, only 1 of the 10 patients achieved a clinical response in these groups. The median progression-free survival time of the placebo group was calculated as 1.5 months in the PALETTE study organized by the EORCT, which led to United States Food and Drug Administration approval of pazopanib (4).

In the χ² analysis performed to compare groups of patients with different histological subtypes, a notably longer progression-free survival was observed in patients with hemangioendothelioma (23 months) and alveolar soft part sarcoma (15 months) compared with that of patients with other subtypes; There were 2 patients in the hemangioendothelioma group and 1 patient did not progress during the 48-month follow-up period. Pazopanib therapy appears to be an ideal option for hemangioendothelioma. In addition, pazopanib therapy has been used as a first-line treatment for alveolar soft part sarcoma (9). The data from the present study therefore supports administering pazopanib as a first-line treatment in metastatic alveolar soft part sarcoma.

It has been demonstrated that low and moderate grade tumors have longer progression free and overall survival under pazopanib therapy (8). However, in the present study, no statistically significant effect of tumor grade on progression-free survival and clinical response was observed. This may have been due to the small number of patients that were evaluated.

Pazopanib is generally not recommended for first-line use in the treatment of soft tissue sarcomas. In the present study, only 3 patients received pazopanib as the first-line treatment. Among them, 2 had alveolar soft part sarcoma and 1 had low-grade leiomyosarcoma. In the analysis, the line of treatment had no effect on progression-free survival or clinical response rates. The fact that these parameters were lower in patients given pazopanib as fourth- or fifth-line treatment was considered to be due to increase in the tumor burden as a result of the increase in the number of failed lines and the worsening of the performance status of the patients. In subtypes in which pazopanib was most often used, such as synovial sarcoma, leiomyosarcoma, pleomorphic sarcoma and angiosarcoma, it still seems to be the most appropriate option after regimens containing anthracyclines and ifosfamide. Furthermore, 3 patients with Ewing sarcoma in the study received this treatment as fourth- or later-line treatment, and 2 had a clinical response (both had isolated lung metastases). There were four different metastatic sites in 1 patient who showed disease progression. It was suggested that pazopanib could also be considered as an option for later-line treatment for patients with Ewing sarcoma whose disease is still under control.

It was predicted that increased tumor burden may adversely affect treatment success, because it is considered that it may be harder to maintain disease control (8). The present analyses demonstrated that the number of metastatic sites affected both progression-free survival and clinical response rates. It was not possible to clearly differentiate between patients with oligometastatic and multimetastatic disease. In the present study, no significant difference was found in the progression-free survival of patients with 0–1 sites and 2 sites. This suggested that patients with ≤2 different metastatic sites could be considered as to have oligometastatic disease.

An advantage of pazopanib over conventional cytotoxic therapies is its tolerance; this is especially true for elderly patients (8). In the present study, treatment tolerance was generally good. The most common adverse effects were hypothyroidism, elevated liver enzyme levels, hypertension, fatigue, diarrhea, hair graying and emesis. This is similar to the side effects reported in another study (10). None of the patients developed grade 3–4 anemia or neutropenia. In 3 patients, pneumothorax and cardiac side effects (arrhythmia and heart failure) developed, and the clinical recommendation was close follow-up of these patients.

In summary, the success of pazopanib therapy and the factors affecting its success have been discussed. Pazopanib therapy was the most successful in patients with alveolar soft part sarcoma and hemangioendothelioma, whereas it was less successful in patients with malignant peripheral nerve sheath tumors and fibrosarcoma.

It was concluded that regardless of the subtype, the response rates of patients with a small number of metastatic sites were improved compared with those of higher number of metastatic sites. In addition, administering the treatment as a second- or third-line treatment appeared to be more successful than administering it as a later-line therapy. Therefore, pazopanib should be evaluated as an option for a selected group of patients in whom the aforementioned factors present together.

Studies to predict the success of pazopanib therapy for soft tissue sarcomas are ongoing. Although there is currently no definitive biomarker to identify patients with soft tissue sarcoma that may benefit from pazopanib therapy, the TP53 mutation status stands out in this regard. A retrospective analysis of 19 patients with advanced soft tissue sarcoma who received pazopanib therapy at the Ohio State James Comprehensive Cancer Center (Columbus, OH, USA) demonstrated a markedly longer median progression-free survival time in the group with TP53 mutations (6). In another retrospective study involving 67 patients at Yonsei Cancer Center (Seoul, South Korea) between 2013 and 2019, biopsy samples were re-examined for programmed death-ligand 1 (PD-L1) expression, and an inverse association was found between PD-L1 expression and the success of pazopanib treatment (11). As a result, a clinical study assessing the use of pazopanib in combination with immune checkpoint inhibitors has been initiated and early results are promising (12); the progression-free suvival was 7.7 months and it was found to be longer compared with that obtained in the EORCT trial and the present study, which were 4.4 and 5 months rescpectively (8,12). As studies on these issues become more comprehensive, clearer data will emerge. Notably, the use of next-generation sequencing technology has become increasingly widespread to provide additional genetic information in cancer treatment (13). In a previous report in which a patient achieved a complete response under pazopanib therapy, several somatic mutations and chromosome amplifications were identified by NGS. For example, somatic mutations, including platelet-derived growth factor receptor α p.T83S and platelet-derived growth factor receptor β exon 13 skipping were found. These findings are consistent with the mechanism of action of pazopanib. Pazopanib is a multiple kinase inhibitor that limits tumor growth by targeting angiogenesis via inhibition of enzymes including vascular endothelial growth factor receptor, platelet-derived growth factor receptor and c-KIT. Patients with these genetic alterations may be better responders to pazopanib therapy (13).

A major limitation of the present study was that it was a single-center, retrospective study. As the study covers patients over a long period, certain patient data could not be accessed, and factors such as tumor grade and treatment tolerance could not be fully evaluated. However, considering how rare sarcomas are and that pazopanib treatment is given only in metastatic disease and generally in later-line therapy, the number of patients increased the reliability and generalizability of the present study. In conclusion, the progression-free survival and response rates of patients with a small number of metastatic sites were better regardless of subtype.