Soft tissue sarcoma (STS) is a highly heterogeneous solid malignant tumor derived from mesenchymal tissue and peripheral nerve tissue, which is clinically uncommon and occurs in adolescents and middle-aged people aged 45-55 years, accounting for 1% of systemic malignant tumors. 30 years ago, local treatment of soft tissue sarcoma relied only on surgery, and the amputation rate was extremely high. An important biological feature of soft tissue sarcoma is local recurrence and late distant metastasis, and most patients die due to distant metastasis of sarcoma. In recent years, with the increasing understanding of the biological behavior of STS, surgery-based comprehensive treatment has been gradually applied in clinical practice, and certain progress has been made, which shows the reduction of amputation rate and recurrence rate, and the improvement of quality of life without affecting the survival rate.
1.Surgical treatment
The key to treating soft tissue sarcoma is early detection and early treatment, and the ideal result depends on the correctness and thoroughness of the first treatment. Surgical resection is difficult to achieve complete resection because the exact histological diagnosis is not available before surgery, and recurrence is inevitable after surgery. The recurrence rate of soft tissue sarcoma has not improved for a long time, which is directly related to the irregularity of surgical treatment and the high rate of positive margins.
Although single surgery is no longer suitable for sarcoma treatment, surgical resection of soft tissue sarcoma is still the most important treatment method, especially for low-grade malignant sarcoma. The common surgical procedures include intracapsular resection, marginal resection, wide excision, radical surgery, limb-preserving tumor segment resection and amputation. Among them, the radical amputation has the lowest local recurrence rate, which is about 5%. In the past two decades, surgical treatment has become more conservative. With the in-depth research on the comprehensive treatment of soft tissue sarcoma, the number of amputations has decreased significantly. Nowadays, amputation is only applicable to those who have huge tumors involving important nerves and blood vessels, with ulceration, infection and bleeding that cannot be controlled; or those whose tumors have threatened patients’ life safety; or those whose tumors have caused adjacent pathological fractures; or those who have undergone distal amputation in the past and now have tumor recurrence and regional lymph node metastasis that cannot be saved by radical surgery or other methods. At present, the treatment of soft tissue sarcoma is mainly to perform the best moderate surgical resection and then supplement with other treatments under the premise of obtaining the same efficacy without damaging the function of the body. With the rapid progress of surgical technology, the boundary between resectable and unresectable soft tissue sarcoma is also being further clarified.
2.Radiation therapy
In recent years, radiation therapy has achieved certain efficacy in the treatment of soft tissue sarcoma, although there are still controversies about the timing and selection of radiotherapy for STS, but scholars agree that the effect is more significant if radiotherapy is added before and after surgery.
2.1 Preoperative radiotherapy
Most scholars believe that preoperative radiotherapy is more beneficial than postoperative radiotherapy for large soft tissue sarcoma with higher malignancy. Proponents believe that preoperative radiotherapy can reduce the scope of surgery, reduce the risk of accelerated tumor proliferation, improve the tumor resection rate, and increase the local tumor control rate. However, the incisional complication rate increases after surgery. However, some overseas scholars have randomly compared the rates of fibrosis, joint stiffness and edema in two groups of patients with 50 Gy preoperative radiotherapy and 66 Gy postoperative radiotherapy for limb STS within 2 years, but the difference was not statistically significant.
2. 2 Postoperative radiotherapy
For refractory cases with high histological grade, the application of postoperative radiotherapy is often necessary and reasonable, and the recent results are satisfactory. However, postoperative radiotherapy can mainly suppress the residual microscopic subclinical lesions, while it is often ineffective for masses and large nodular tumors. Also, the target area of postoperative radiotherapy is larger, and the incidence of late complications such as fibrosis, joint stiffness and edema is higher than that of preoperative radiotherapy. Nevertheless, some scholars still recommend postoperative radiotherapy, and believe that preoperative radiotherapy should only be used for sarcomas that are impossible to resect and those with poorly defined primary tumors. In recent years, radiotherapy-assisted surgery has become the standard treatment for intermediate to high-grade sarcomas of any size. However, radiation therapy is not necessary for tumors smaller than 5 cm due to their low recurrence rate.
2. 3 Tissue interstitial postmount radiotherapy
Since post-mounted irradiation takes advantage of the increased sensitivity of tumor cells in fresh wounds under aerobic conditions and enhances the targeting of radiotherapy by intraoperative direct visualization, coupled with external irradiation after wound healing, it is more effective in controlling and killing residual cancer cells in the tumor bed to compensate for surgical resection, thus achieving a curative effect, especially for G223 sarcoma. Siddhartha et al.
After a median follow-up of 45 months, we found that the DFS of superficial tumors was better than that of deep tumors (P = 0. 02), the OS of patients with tumors smaller than 5 cm was significantly better (P = 0. 05), and there was a significant advantage in LC, DFS, and OS at irradiation doses greater than 60 Gy (P < 0. 05). (P < 0. 05). Subcutaneous fibrous degeneration was the main complication.
3. Chemotherapy
STS is a very heterogeneous tumor, and different histological types, different sites, different pathological grades and different sizes of tumors may have different effects on chemotherapy. Chemotherapy-based combination therapy has been shown to be effective for rhabdomyosarcoma and Ewing’s sarcoma, but the effect on most adult STS has not been fully confirmed.
3.1 Effective drugs
In the past 10 years, the effectiveness of chemotherapy has been significantly improved by the application of adriamycin and isocyclophosphamide. As an adjuvant therapy to surgery, the role of combination chemotherapy in controlling local recurrence and distant metastases has been recognized by most people, but whether it can prolong survival remains controversial. However, so far, only a few drugs such as adriamycin, isocyclophosphamide and azulfiram can achieve an efficiency of about 20%, and the development of new
The development of new effective drugs is the focus of future research.
In recent years, new drug studies have found that doxorubicin liposomes have comparable efficacy to adriamycin, which can be considered for patients who cannot tolerate high-dose chemotherapy, especially for patients with cardiotoxic sensitivity to standard doses of adriamycin. In the study of angiosarcoma, the efficiency of paclitaxel and doxorubicin liposomes in the treatment of angiosarcoma was found to be high, especially paclitaxel was up to 89%, and the toxic side effects were less than those of adriamycin and isocyclophosphamide.
Therefore, paclitaxel can be used as the first-line drug for the treatment of certain angiosarcomas.
The effectiveness of doxorubicin combined with pegylated glycosides in the treatment of 20 advanced or large adult soft tissue sarcomas that had previously failed to receive adriamycin or standard doses of isocyclophosphamide was 33%, and the relationship between dose and efficacy was confirmed by Jiang Shoujun et al.
3. 2 Timing of chemotherapy
3. 2. 1 Preoperative chemotherapy (neoadjuvant chemotherapy) Although there are inconsistent conclusions regarding preoperative chemotherapy, most scholars agree that preoperative chemotherapy is more effective in controlling and treating small metastases in large, highly malignant advanced or metastatic soft tissue sarcomas, significantly reducing the size of the primary foci, facilitating surgery, avoiding accelerated growth of latent secondary foci after resection of the primary foci, and making the tumor cells less likely to spread during surgery. The tumor cells are less active and less likely to spread
The tumor cells are less active and less likely to spread into the bloodstream during surgery. Recently, Bernd Kasper et al. performed 4 cycles of neoadjuvant chemotherapy EIA vp16 + ADM + IFO followed by surgery in 21 patients with high-risk soft tissue sarcoma and concluded that the median overall survival of all patients was >21.6 months with an efficiency of 43% and 62% of patients were able to undergo R0 resection after 4 cycles of neoadjuvant chemotherapy. In conclusion: neoadjuvant chemotherapy can reduce the stage of tumor, thus allowing patients to benefit in the long term.
3. 2. 2 Interventional chemotherapy
3. 2. 2 Interventional chemotherapy Intra-arterial drug delivery includes arterial infusion (with or without tourniquet) and isolated perfusion of the limb or organ, mostly for larger primary or recurrent STS, with the aim of avoiding amputation by limb-sparing surgery as much as possible. The local drug concentration of regional arterial perfusion can be 10-30 times higher than that of systemic intravenous administration, allowing control of areas with active tumor margin growth. In recent years, the combination of heating, chemotherapy and biological therapy has been applied abroad.
In recent years, the combination of heating, chemotherapy and biotherapy with perfusion has been applied overseas for better efficacy. In addition, in addition to interventional chemotherapy, the drug concentration and efficacy can be significantly improved by heating and perfusion.
3. 2. 3 Postoperative chemotherapy Postoperative adjuvant chemotherapy has been debated, especially for visceral and retroperitoneal soft tissue sarcomas. Evaluating the role of chemotherapy in STS is difficult. Even so, chemotherapy is widely used in the treatment of unresectable STS and is of great importance in preserving organs and increasing the likelihood of surgical resection, while postoperative adjuvant chemotherapy, as an important component of comprehensive treatment, is important in eradicating subclinical lesions and reducing or delaying
The role of postoperative adjuvant chemotherapy, as an important part of comprehensive treatment, can not be ignored in eliminating subclinical lesions and reducing or delaying distant metastasis and recurrence.
4.Targeted therapy
In the study of gastrointestinal mesenchymal cell sarcoma, it was found that the targeted therapy drug Imatinib has good efficacy, high safety and good tolerability in the treatment of progressive GIST. However, during the treatment process, some patients were initially sensitive to this drug and then experienced disease progression. Patients who are resistant to one kinase inhibitor have been found to benefit clinically from another multi-targeted tyrosine kinase inhibitor, and sunitinib falls into this category. Sunitinib is effective in those who are intolerant to imatinib or whose disease progresses after imatinib by inhibiting tumor blood vessel growth and preventing tumor cell reproduction. A recent multicenter, randomized, double-blind, placebo-controlled phase III clinical study (Study A6181004) compared time to disease progression, progression-free survival, and overall survival in the sunitinib (sunitinib) + best supportive care group versus the placebo + best supportive care group.
The results showed that sotan significantly delayed the time to disease progression, prolonged progression-free survival, and significantly improved overall survival in GIST patients, reducing the risk of death by 51%.
ET2743 is effective in unresectable soft tissue sarcomas by up to 20% and in some drug-resistant tumors. A 2008 phase I study of ET2743 in combination with adriamycin for recurrent refractory soft tissue sarcoma demonstrated that adriamycin 60 mg/m2 combined with ET2743 1. 1 mg/m2 in 21-day cycles was safe and effective.
In addition, data from a phase II clinical study of ABT2510, an analog of the natural anti-angiogenic protein platelet thrombospondin 1 (Thrombospondin21), have demonstrated a satisfactory safety profile for both the low-dose (20 mg/day) and high-dose groups (200 mg/day) of ABT2510. The median disease-free survival of ABT2510 for recurrent or unresectable soft tissue sarcoma in the low-dose and high-dose groups was
The median disease-free survival at 4 months was 42% and 41%, and the median survival was 431 and 295 days, respectively, but the objective remission rate was lower.
Zeming et al. found overexpression of Midkine (MK) gene in several human soft tissue sarcomas, and they found meaningful elevation of MK in the nucleus of metastatic tumors when monitoring MK on tissue microarrays in rhabdomyosarcoma, and the final results suggest that overexpression of MK gene can promote the growth of soft tissue sarcoma, and also suggest that MK gene and its receptor can be used as a new therapeutic target in the future. The final results suggest that MK gene overexpression can promote the growth of soft tissue sarcoma, and also suggest that MK gene and its receptor can be used as new therapeutic targets for soft tissue sarcoma.
With the progress of molecular biology of tumor, we have reason to believe that molecular targeting of tumor therapy will play a greater role in the treatment of STS.
5.The choice of comprehensive model
Currently, the central issue in the treatment of soft tissue sarcoma remains how to improve the quality of life of patients through more reasonable cooperation among various disciplines, while further improving and stabilizing the survival rate and reducing the recurrence rate, and at the same time increasing the limb preservation rate. The choice of a comprehensive model is not unanimous, but requires a combination of factors such as tumor grade, size, extent of invasion, complications, patient’s physical condition, and the choice of treatment goals. In general, it is believed that for sarcoma with low grade and tumor diameter ≤ 5 m, wide excision should be the main treatment, but when the tumor is > 5 cm, radiotherapy and/or chemotherapy should be added once the residue is suspected in combination with intraoperative findings; for sarcoma with high grade, wide excision + radiotherapy + chemotherapy should be used when the tumor diameter is ≤ 5 cm; for > 5 cm, radiotherapy + thermotherapy + surgery + chemotherapy should be used; when the tumor involves blood vessels and nerve trunk, radiotherapy should be used as much as possible. If the tumor involves blood vessels and nerve trunk, interventional chemotherapy + thermotherapy + surgery + radiotherapy should be adopted to preserve the limb as much as possible.
In conclusion, although the treatment level is improving, there is still much room for improvement in the treatment mode of soft tissue sarcoma. Comprehensive treatment has become an important tool to improve the prognosis of soft tissue sarcoma. Especially for highly malignant sarcomas, a joint consultation including surgery, pathology, radiotherapy, chemotherapy, and plastic surgeons is advocated to develop a full treatment plan. Preoperative interventional chemotherapy and preoperative radiotherapy often make some difficult to resect sarcomas resectable, and postoperative radiotherapy can reduce recurrence in sarcomas with positive margins. Most of the recent studies have demonstrated the effect of chemotherapy on improving sarcoma survival, overall survival, and controlling recurrence and metastasis, but the statistical significance is not significant. The trend of the previous 20 years to focus on radiotherapy is likely to shift to a future emphasis on the role of induction chemotherapy, but prospective studies are still needed on the prospect of both truly affecting recurrence and survival.