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The completeness of the surgical removal has impact on local tumor control and patient survival, especially in high-grade soft tissue sarcomas. However, even with complete resection, 20-40% of patients develop local recurrences. Radiotherapy halves this rate, particularly through preoperative use; nevertheless, even in studies, the rate of local recurrence is rarely below 15%, which needs improvement.

This is where locally synergistic therapies gained importance. There are many years of experience with anthracyclines, ifosfamide or trabectedin. Their additive effect results from cellular damage patterns that are comparable to those of radiation therapy. Recent findings from an unplanned analysis of the GEIS study showed a very low long-term local recurrence rate of 5% for a concurrent administration of doublet chemotherapy together with a conventional fractionated radiotherapy compared to a sequential administration. The fact that cytostatics can be administered without dose compromises makes the concept interesting not only for borderline resectable tumors, but also for high-grade sarcomas in general, which are most likely to benefit from early and uncompromising chemotherapy. Simultaneous therapy concepts without dose compromises also seem to be possible with trabectedin. High rates of pCR (>10%) can also be achieved with pazopanib or the intralesional use of NBTXR3 and this without significant additive local toxicity. However, the clinical horizon of experience is small.

In addition, regional hyperthermia is considered to act as radio- and chemosensitizer. For the latter, data on improved local control and survival compared to perioperative chemotherapy alone are available from an EORTC-Trial. Synergistic effects result, for example, from thermally induced increased alkylation. The effects of radiotherapy are also increased by hyperthermia, particularly in hypoxic areas and based on impaired DNA-repair mechanisms and the emission of immunogenic damage signals. Cohort studies show a comparable effect of chemoradiotherapy and radiothermotherapy in sarcomas. Ultimately, the option of their combined use in high-grade sarcomas results from the favorable toxicity profile of hyperthermia and chemoradiotherapy, which is now considered feasible. Although the data on this is still sparse, neoadjuvant triplet therapy shows a further increase in pathological remission. This makes the application of the concept interesting for studies on multimodal therapy of soft tissue sarcomas.