Systemic treatment options for patients with refractory adult-type sarcoma beyond anthracyclines

Abstract

For the subgroup of patients with inoperable gastrointestinal stromal tumors, progress has been made by the rapid development and approval of the targeted therapy imatinib mesylate. Small round cell sarcoma, such as Ewing/PNET, desmoplastic small round cell sarcoma and rhabdomyosarcoma, are chemotherapy-sensitive and potentially curable malignancies, which are treated with multimodality, dose-intensitive and neoadjuvant protocols regardless of size or overt metastatic disease. A limited number of effective agents available for the treatment of patients with metastatic adult soft-tissue sarcoma exists, which have failed anthracyline and ifosfamide-based chemotherapy. Most other high-grade (grading >I) so-called adult-type soft-tissue sarcomas such as fibro, lipo, pleomorphic and synovial sarcoma are treated with a anthracycline-based regimen with or without ifosfamide as front-line therapy. In this review, the therapeutic activities of drugs currently available as second-line treatment in patients with metastatic soft tissue sarcoma are summarized, providing an overview of contentious or emerging treatment issues. In relapsed 'adult-type' soft-tissue sarcomas trofosfamide, gemcitabine and ecteinascidin (ET-743) appear to be drugs associated with moderate activity and an acceptable toxicity profile. An interesting finding to be noted is that the different drugs have particular effects in distinct subtypes of soft-tissue sarcoma; however, it has to be taken into account that the number of patients included in those phase II trials are limited. The role of the newer agents (e.g. patupilone derivates, brostallicin) is currently not definable. The so-called selective therapy targeting vascular endothelial growth factor (receptor), epidermal growth factor receptor, c-kit, Raf kinase or platelet-derived growth factor receptor and bcl-2 antisensing, proteasome, protein kinase C/B, and mammalian target of rabamycin inhibition will continue to be tested in gastrointestinal stromal tumors patients refractory to imatinib mesylate as well as in selected sarcoma subtypes.

Primary intracranial soft tissue sarcomas in children, adolescents, and young adults: single institution experience and review of the literature

“…PDGFRA and its downstream effectors, mitogen-activated protein kinase and Akt, were highly activated in both primary and meta-static tumors. Inhibition of PDGFRA had a dramatic effect on tumor cell growth, both in vitro and in vivo, and has proven beneficial in several types of sarcomas [11, 15, 17, 19, 24, 25, 27, 28]. …”

“…Increasing knowledge of potential molecular targets along deregulated cellular pathways has helped to profile the development of novel therapies in sarcomas [23, 25, 28]. This small yet relevant study defines the importance of elucidating molecular biology in the armamentarium of IS diagnosis to enable us to add targeted therapy to the backbone of conventional treatment strategies.…”

Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study

“…Systemic treatment options for refractory advanced sarcoma are limited and the prognosis for these patients is poor 1. A substantial proportion of sarcomas seem to be driven by chromosomal translocations or specific pathways, with characteristic molecular events2 that could be new targets for therapy.…”

Definitive radiotherapy and Single-Agent radiosensitizing Ifosfamide in Patients with localized, irresectable Soft Tissue Sarcoma: A retrospective analysis

“…Adjuvant chemotherapy is applied by some groups in selected patients with sarcomas of the extremities in high risk situations, for example deep location, grade 2 and 3 and size larger than 5 cm [2-4]. Despite all efforts, the prognosis, especially for advanced high grade sarcomas, is still limited.…”