Neoadjuvant Treatment of Locally Advanced Soft Tissue Sarcoma of the Limbs: Which Treatment to Choose?

Soft tissue sarcomas (STSs) form a heterogeneous group of malignant neoplasms arising in the mesenchymal connective tissues. They can develop at any anatomic site but 60% occur in the extremities. Initially, treatment of STS relied solely on excision. In the 1970s, Enneking et al. developed the concept of compartmental resection to reduce the local failure rate. Later, Rosenberg et al. demonstrated, in a randomized study, that there was no difference in local tumor control and disease-free survival (DFS) in patients treated with amputation versus limb-saving surgery followed by 50-70 Gy external-beam radiotherapy (EBRT). A considerable proportion of patients present with locally advanced tumors as a primary or recurrent disease and cannot be resected with adequate clearance margins. These patients are threatened with amputation for complete tumor removal. Improvements in surgical techniques, such as microvascular muscle flaps, allow for the avoidance of limb loss in the majority of cases. However, the use of frozen sections to determine intraoperatively whether clear margins have been achieved is limited by the multiplanarity of resection specimens. Thus, local failure rates are 15%-25%, and preoperative measures to sterilize the invasive margin of sarcomas have been explored. High-dose preoperative EBRT for high-grade STS was developed, and its combination with intra-arterial or i.v. chemotherapy was reported to be effective. Recently, systemic chemotherapy combined with deep wave hyperthermia was shown to result in a longer DFS time in a large, randomized, phase III study. Treatment concepts differ significantly among centers and are influenced more by availability of technical equipment than by data. It is the aim of this review to elucidate the rationale of different regimens and analyze their potentials as well as weaknesses.