Sarcoma is a rare malignant tumor originated from mesenchymal tissue. For advanced, unresectable sarcomas, systemic chemotherapy is the most common method. However, the m-OS of patients with advanced sarcoma is about 12 months, and the 5-year survival rate is less than 10% . In addition, the sensitivity of different subtypes of sarcoma to chemotherapy is different, and the adverse events of chemotherapy are large, which hinders the application of systemic chemotherapy. Therefore, it is urgent to find a more effective treatment for patients with advanced sarcoma.
A large number of studies have confirmed that angiogenesis plays a significant role in the occurrence, progression and metastasis of tumor . It has been reported that overexpression of VEGF is associated with early recurrence, metastasis and low survival rate of sarcoma . Therefore, targeted therapy for VEGF / VEGFR is a feasible treatment. At present, small molecule targeted drugs TKIs have been used in the treatment of sarcoma, and have shown good results, including pazopanib, apatinib, sunitinib, and anlotinib [20, 27, 29–32]. Pazopanib is the only antiangiogenic drug approved for sarcoma. In the palette clinical trial of pazopanib , 6% of patients were evaluated as PR after pazopanib was used, 67% were evaluated as SD, and 23% were evaluated as PD, with m-PFS of 4.6 months. Another pazopanib clinical study  reported that 15.6% of patients were evaluated as PR, 39.2% were assessed as SD, m-PFS and m-OS were 5.3 months and 12 months respectively. Two other studies on pazopanib have also produced similar results [34, 35]. Liu et al.  reported that the ORR, m-PFS and m-OS of apatinib in the treatment of sarcoma were 23.68%, 7.87 and 17.55 months, respectively. Several other studies of apatinib also reported similar results [13, 17, 36, 37]. There are also studies reported that after treatment with sunitinib, 1.8% of patients reached PR, and 20% of patients achieved SD .
Anlotinib is a novel oral drug targeting VEGFR-1/-2/-3, platelet-derived growth factor receptor α/β, c-kit and other targets. It has dual effects of inhibiting tumor cell proliferation and tumor angiogenesis.It has been approved by China Food and Drug Administration for second-line treatment of advanced and metastatic sarcoma in 2019 [39, 40]. Chi et al.  reported that anlotinib showed a good therapeutic effect in the treatment of sarcoma. A total of 166 patients were enrolled in the study, with ORR of 13%, m-PFS of 5.6 months, and m-OS of 12 months. Patients with different subtypes of sarcoma showed different therapeutic effects.
This study evaluated the efficacy and safety of monotherapy with anlotinib in 45 patients with sarcoma. The results showed that the ORR and DCR were 6.82% and 81.82% after 3 months of treatment. The total ORR, DCR and m-PFS were 2.27%, 27.27% and 5.71 months after the end of treatment. In this study, the efficacy of anlotinib was slightly better than pazopanib and sunitinib, but similar to that of apatinib in the treatment of sarcoma, DCR and m-PFS were similar. Unfortunately, the ORR in this study is lower [13, 17, 22, 30, 33–38]. In addition, the efficacy of this study is similar to that reported by Chi  in the treatment of sarcoma. Although ORR is low, m-PFS is slightly longer.
In this study, the analysis of the influencing factors of PFS showed that there were differences in the efficacy of different subtypes of sarcomas treated with anlotinib. The efficacy of ASPS patients was the best, and the m-PFS reached 8.07 months, which was significantly better than that of other subtypes of sarcomas. Previous studies have also reported the good efficacy of TKI in the treatment of ASPS. For example, Stacchiotti S et al. reported that the m-PFS of sunitinib in the treatment of ASPS was 17 months. Also, Stacchiotti S et al.  reported that the m-PFS of pazopanib in the treatment of ASPS was 13.6 months, and Wang et al reported that the m-PFS reached 18.53 months after apatinib in the treatment of ASPS, while in another study of anlotinib in the treatment of ASPS, m-PFS even reached 21 months . The reason why the therapeutic effect of ASPS is better than that of other subtypes of sarcoma after TKI treatment is not completely clear, and it is believed that it may be related to the following reasons: First, ASPS is considered to be an inert sarcoma , so the survival time of patients with ASPS is longer than that of patients with other subtypes of sarcoma; Secondly, due to the high heterogeneity of sarcomas, the sensitivity of different subtypes of sarcomas to TKI is different, so it is necessary to further study the sensitivity of different sarcoma targets.
A number of studies have reported that the ORR of metastatic STS treated with apatinib is higher than that of osteosarcoma, while there is no significant difference in DCR, m-PFS, m-OS between the two groups [12, 22, 44]. However, Zhu et al.  reported that compared with osteosarcoma, apatinib has a tendency to improve the PFS of STS. In this study, the m-PFS of osteosarcoma after the administration of anlotinib was 2.86 months, and the curative effect was not as good as that of ASPS, SS, FS and UPS, which was similar to what Zhu et al. reported. The reason for the difference between the efficacy of anlotinib in the treatment of osteosarcoma and STS is not clear, which may be related to the following reasons: Firstly, the biological characteristics of osteosarcoma and STS are different, which leads to different sensitivity to anlotinib [29, 45]; Secondly, the prevalence of osteosarcoma is different from that of STS. Osteosarcoma is more common in children and adolescents, while STS is more common in adults. Due to the differences in physical condition, physiological mechanism and immune function between children and adults, it may lead to different therapeutic effects after the application of anlotinib. Thirdly, there are also obvious differences in genetics and genomics, which may lead to differences in sensitivity and efficacy of targeted drugs [46–48].
In this study, the safety of anlotinib monotherapy in the treatment of sarcoma is good, most patients only have grade 1 and 2 adverse events. The most common adverse events were hypothyroidism (increased TSH), anemia, fatigue, loss of appetite, decreased liver function, leukopenia and hand-foot syndrome, which were similar to the previously reported adverse reactions of anlotinib in the treatment of sarcoma and lung cancer [11, 27, 49, 50]. It is worth noting that one patient developed severe myelosuppression, which was also reported in the study of Wang et al. . Therefore, during the treatment, it is necessary to timely monitor the blood routine and other examinations of the patients, and timely find and deal with myelosuppression.
Liu et al.  found that the OS of patients with AES such as hypertension, hand-foot syndrome and proteinuria after treatment with apatinib was longer than that of patients without these AES, while there was no significant difference in ORR, DCR and PFS. Liao et al.  also reported similar findings. In this study, many patients did not achieve OS, so the relationship between AES and OS could not be evaluated. However, in this study, the PFS of 4 patients with hand-foot syndrome was significantly longer than that of the patients without hand-foot syndrome (12.55 months vs 5.07 months, P = 0.036) (Fig. 2D). The reasons for the relationship between AES and clinical outcomes are still unclear, and further studies are needed to clarify the relationship.
There are some limitations in this study. First of all, this study is a retrospective study, and there is no control. Secondly, there are few patients in some subtypes. Because of the heterogeneity of sarcomas, the results may be affected in the efficacy analysis among different subtypes. Thirdly, the patients received different treatment regimens, which may have an impact on the results of this study. Finally, this study was limited to clinical evaluation, and no target and molecular biology monitoring studies were conducted.