Soft tissue sarcomas (STS) are a group of mesenchymal malignant tumors originating from soft tissues and visceral organs, with a wide range of origins and varying histological manifestations. Due to the low incidence of STS and clinical conditions, this type of tumor is incompletely understood. Since soft tissue sarcoma often undergoes systemic dissemination and lung metastasis can also be seen in the early stage, isolated lung metastases are still advocated to be surgically resected, while all others require pharmacological treatment. It is especially important to choose appropriate drug therapy for patients with advanced and refractory soft tissue sarcomas that are not suitable for surgery or resistant to commonly used chemotherapeutic agents. Among them, some soft tissue sarcomas such as rhabdomyosarcoma and Ewing family tumors have significant therapeutic effects of chemotherapy. In recent years, new drugs acting on different targets have entered clinical studies one after another and have been initially shown to be effective in soft tissue sarcomas. These include: paclitaxel, liposomal doxorubicin, gemcitabine, topotecan, ET-743 (Trabectedin,Yondelis), etc. The diagnosis of STS combined with comprehensive analysis of clinical, pathological and imaging In 2008, the number of cases of STS in the United States was 10,390, and the incidence of STS in Europe was 8,000-9,000 cases/year. Epidemiologic statistics are lacking in China, but the incidence rate is estimated to be similar to that of the United States and Europe (approximately 2-3/100,000). According to the literature, the incidence of soft tissue sarcoma accounts for about 1% of all malignant tumors. Currently, soft tissue sarcomas are clinically classified as: adult soft tissue sarcomas (accounting for 1% of adult malignant tumors, including liposarcoma, synovial sarcoma, smooth muscle sarcoma, fibrosarcoma, malignant fibrous histiocytoma, and malignant nerve sheath tumors, etc.), Ewing family of tumors [including typical Ewing’s sarcoma and peripheral primitive neurectodermal tumors (p-PNET), which are mostly seen in children and adolescents], rhabdomyosarcoma (a small round-cell tumor with extremely high degree of malignancy), and rhabdomyosarcoma (a small round-cell tumor with high degree of malignancy). highly malignant small round cell tumors, common in pediatric patients), and other rare sarcomas. The development of soft tissue sarcomas is a gradual spread from a localized stage to a systemic one, manifesting primarily as soft tissue swelling and/or deep masses. The localized stage of sarcoma that occurs in adults and some pediatric patients lasts longer. The most common sites of metastasis are the lungs first, followed by bone, liver and other organs, and regional lymph nodes are less frequently involved. At present, the diagnosis of soft tissue sarcoma relies on the morphological manifestations under light microscope, not only using special staining, immunohistochemistry and electron microscopy for pathological diagnosis, but also combining with clinical and imaging (age, tumor size, location, growth mode, imaging characteristics, etc.) to make a correct diagnosis.STS therapeutic drugs tradition and progress of traditional cytotoxic drugs: the power of the single force is weak, and at present, there are only a few kinds of drugs effective for soft tissue sarcoma. Currently, there are only a few drugs that are effective for soft tissue sarcoma, including anthracyclines such as doxorubicin, epirubicin, and pilocarpine; and alkylating agents such as cyclophosphamide, isocyclophosphamide, and azelnidazole. The effectiveness rate of single drug is between 14% and 30%. The efficacy of first-line chemotherapy is best with doxorubicin and isocyclophosphamide. Anthracyclines were the first single agents applied to soft tissue sarcomas. Combination regimens based on the representative anthracycline drug doxorubicin, such as AD (doxorubicin + azelnidazole), AIM (doxorubicin + isocyclophosphamide + mesna), and MAID (doxorubicin + isocyclophosphamide + azelnidazole), can result in an efficacy rate of up to 40% for soft tissue sarcoma. Alkylating agents have also shown definite efficacy in STS. Among them, isocyclophosphamide, an isomer of cyclophosphamide, is more effective than cyclophosphamide in soft tissue sarcoma. Isocyclophosphamide can cause adverse effects such as hemorrhagic cystitis, and can be used effectively to protect the mucosal epithelium of the urinary tract by combining it with sodium 2-mercaptoethyl sulfonate (Mesna). The isocyclophosphamide combined with doxorubicin regimen is currently the first-line regimen for chemotherapy of soft tissue sarcoma. However, the emergence of drug safety and drug resistance has limited the use of such drugs in the treatment of advanced relapsed refractory STS, and there is an urgent need to develop novel second-line STS therapeutic drugs. Novel drugs: a heavy responsibility with high expectations Under the joint development of clinical and basic research, new drugs acting on different targets have entered clinical research one after another, and initially shown to be effective in soft tissue sarcoma. These include: liposomal doxorubicin, paclitaxel, ET-743, gemcitabine, topotecan, imatinib and so on. Liposomal doxorubicin is superior to doxorubicin in that the polyethylene glycol coat of the drug can significantly prolong the half-life of the drug, reduce the systemic toxicity, easy to be absorbed by tumor tissues, and highly efficient and low toxicity. Phase II clinical studies have shown that liposomal doxorubicin has similar efficiency to doxorubicin, but can be used as a first-line option for patients with cardiac disease and elderly patients who cannot tolerate high-dose chemotherapy. Studies have shown paclitaxel to be effective in hemangiosarcomas other than those of the head and face, but less so in other soft tissue sarcomas. Therefore, paclitaxel is used clinically as a first-line agent for the treatment of some hemangiosarcomas. Whether gemcitabine is effective for soft tissue sarcomas is still controversial, and some researchers believe that gemcitabine combined with paclitaxel is effective for some smooth muscle sarcomas. Topotecan, irinotecan, and lubitecan are DNA topoisomerase I inhibitors, and are currently used to treat children’s soft tissue sarcomas of higher malignancy or as adjuvants to chemotherapy for progressive sarcomas or sarcomas after recurrence. Imatinib mesylate is a molecularly targeted drug with excellent therapeutic effects on gastrointestinal mesenchymal tumors, and consensus has identified this drug as a first-line agent for the treatment of gastrointestinal mesenchymal sarcomas. ET-743 is a novel anticancer drug extracted from the alkaloids of Ascidiaceae, which is the only drug approved for the treatment of STS in the past 20 years, with a unique mechanism of antitumor action.ET-743 kills tumor cells by binding to the minor groove region of DNA and interacting with DNA repair enzymes and transcription factors, interfering with different cell cycles. Anti-tumor activity studies have shown that ET-743 is more active than widely used anticancer drugs, such as paclitaxel, camptothecin, doxorubicin, mitomycin, cisplatin, etc. ET-743 has a very strong anti-tumor activity against certain tumor cell lines, including STS, ovarian cancer, and breast cancer. Among them, the sensitivity of STS tumor cell lines to ET-743 is very high (IC50 of 0.0002~0.3 nM), much greater than that to doxorubicin or paclitaxel. Due to the unique mechanism of action of ET-743, superimposed or synergistic anti-tumor effects can be observed when combining it with other cytotoxic agents such as cisplatin, doxorubicin and paclitaxel, and the European Union has approved ET-743 as an effective drug for the treatment of soft tissue sarcoma. Phase II clinical trials have shown that the drug has a 6-month PFS rate of 39% for the treatment of advanced soft tissue sarcoma that is ineffective with first-line chemotherapy, and it can prolong patient survival, with a median survival of 13.8 months and a 1-year survival rate of 61%, which undoubtedly provides a promising option for patients with advanced and refractory soft tissue sarcoma, especially those who have failed to undergo treatment with isocyclophosphamide and doxorubicin.Reasonable STS treatment strategy The treatment strategy of STS determines the prognosis The treatment plan for sarcoma requires the collaboration of surgeons, medical oncologists, radiotherapists, and other specialists. Therefore, it is recommended that sarcoma patients consult a large, specialized medical institution that has a strong overall practice and is more experienced in treating sarcomas. Although soft tissue sarcomas can be removed with appropriate surgical procedures, there is still a high risk of recurrence and eventual death in cases with high-risk factors, such as large or deeply invasive tumors. Adjuvant chemotherapy is highly recommended in high-risk sarcoma cases. High-dose isocyclophosphamide (>12-14 g/m2) has been shown in the literature to be effective in patients with drug-resistant soft-tissue sarcomas, but toxicity is also a factor to consider. ET-743, which is already available in the EU, could be an option for second-line treatment in patients with advanced STS due to its better activity and survival benefits. All Ewing family tumors require a combination of therapeutic approaches. Induction chemotherapy is usually given first. This includes chemotherapy regimens with drugs such as doxorubicin, isocyclophosphamide, actinomycin D, etoposide ± vincristine. After induction chemotherapy, in the case of localized lesions, radiotherapy is given, on the basis of which surgical treatment is combined. Treatment of rhabdomyosarcoma also involves multiple disciplines and most commonly includes surgical treatment, chemotherapy and radiotherapy. Conventional chemotherapy includes cyclophosphamide, vincristine, and actinomycin D. The combination of isocyclophosphamide and etoposide has been reported to be sensitive for rhabdomyosarcoma. Surgical resection in patients who achieve remission with first-line chemotherapy is sufficient to eradicate the tumor, and to assess whether chemotherapy has induced the tumor to achieve complete pathological remission. Wide excision of the lesion is generally advocated, but surgical approaches for tumors in specific areas such as the head and neck require further consideration. Chemotherapy and radiotherapy are preferred for patients in whom surgery would result in severe injury such as rhabdomyosarcoma occurring in the orbit. Postoperative adjuvant chemotherapy: anthracycline- and isocyclophosphamide-based chemotherapy is standard A portion of soft tissue sarcomas may have localized or limited recurrence after initial treatment, but it is uncontrolled micrometastases or large systemic metastases that are the real threat to the patient’s life. Therefore, whether the early application of systemic therapies can affect micrometastases and thus improve overall and disease-free survival remains a question worth exploring. Adjuvant or neoadjuvant chemotherapy is the appropriate standard of care for Ewing sarcoma/primitive neuroectodermal tumor (PNET) and rhabdomyosarcoma. However, for most soft tissue sarcomas such as smooth muscle sarcoma, liposarcoma, and highly differentiated malignant fibrous histiocytoma (MFH), the benefit of chemotherapy is less. The benefit of adjuvant chemotherapy is relatively small for common early-stage tumors, such as Stage I breast cancer and Stage II colon cancer, so the principle of individualization of chemotherapy for patients with soft-tissue sarcomas also needs to be adopted. Although there is a lack of effective drugs to stop disease progression in metastatic sarcomas, the success of imatinib in treating gastrointestinal mesenchymal stromal tumors holds the promise of new systemic drug therapies. The ultimate goal of chemotherapy is to improve the cure rate of patients. Currently anthracycline- and isocyclophosphamide-based chemotherapy are the standard postoperative adjuvant chemotherapeutic agents for soft tissue sarcomas. Since the introduction of doxorubicin, there have been more than 12 clinical studies of anthracycline-based adjuvant chemotherapy for soft-tissue sarcomas, and several studies have shown that chemotherapy can increase 10-year disease-free survival from 45% to 55% and localized disease-free survival from 75% to 81% in soft-tissue sarcomas. Importantly, the 10-year overall survival rate increased from 50% to 54%, and although the difference was not statistically significant, there was a clear trend toward higher rates. Preoperative neoadjuvant chemotherapy: first-line chemotherapy routinely using isocyclophosphamide and epirubicin Preoperative chemotherapy is theoretically superior to postoperative chemotherapy. First, preoperative chemotherapy provides evidence of in vivo chemosensitivity. Patients with effective preoperative chemotherapy are more likely to benefit from postoperative chemotherapy. It can be hypothesized that patients with ineffective preoperative chemotherapy will have little or no benefit from postoperative chemotherapy and will simply suffer a toxic response to chemotherapy. A second advantage of preoperative chemotherapy is that it can be used to treat micrometastases as early as possible after the tumor diagnosis has been made or to prevent the progression of micrometastases after surgery. The third advantage of preoperative chemotherapy is that chemotherapy reduces the size of the tumor, allowing for a smaller postoperative radiotherapy field, and also allows for incompletely resectable tumors to become completely resectable. For giant soft tissue sarcomas of the limb, chemotherapy can reduce postoperative complications after limb-sparing surgery and even enable patients who need amputation to undergo limb-sparing surgery. Recently, combination regimens of anthracyclines and isocyclophosphamide have been used for preoperative chemotherapy. Patients receiving isocyclophosphamide-based chemotherapy have had significant remission rates, and preliminary results suggest that remission rates may be higher than historical controls without isocyclophosphamide. In conclusion, there are few effective chemotherapeutic agents available for STS patients.First-line chemotherapy such as isocyclophosphamide and epirubicin are routinely used in the clinic, and there are few good second-line therapeutic agents available for patients with advanced STS who have failed first-line therapy or who have developed a poor prognosis of drug resistance.Clinical use of ET-743 has treated more than 2,000 cases worldwide, and the drug has a high rate of tumor control, providing a very promising opportunity for STS patients a very promising option.