Emerging therapies for adult soft tissue sarcoma

Abstract

Soft tissue sarcoma (STS) are a broad group of rare tumors. Cornerstone of treatment is surgery. Complementary radiotherapy is recommended in high-risk STS arising from extremities. Doxorubicine ± ifosfamide based cytotoxic chemotherapy, explored in few randomized trials, showed a certain degree of activity, playing an established role only in unresectable disease. Since peculiar chemosensitivity towards alternative drugs was described for different metastatic subtypes in second or further lines, the modern concept of ‘histology-driven chemotherapy’ has been accepted and employed: gemicitabine ± dacarbazine, trabectedin and taxanes used respectively in patients with leiomyosarcoma, solitary fibrous tumor, myxoid/round cell liposarcoma, angiosarcoma. Recent discoveries about molecular pathways involved in STS tumorogenesis led to develop molecular targeted agents such as imatinib used in advanced dermatofibrosarcoma protuberans (DFSP) or metastatic DFSP-related fibrosarcoma, pazopanib, approved as second line regimen in advanced non-adipocitic STS and recently sunitinib in solitary fibrous tumors, alveolar soft part sarcoma and extraskeletal myxoid chondrosarcoma.

Keywords::

• adjuvant
• chemotherapy
• doxorubicin
• ifosfamide
• imatinib
• neoadjuvant
• palliation
• sarcoma
• trabectedin
• trgeted therapy

Financial & competing interests disclosure

A Gronchi has received honoraria from Novartis Pharma and received payment for the development of educational presentations from Novartis Pharma, PharmaMar and Pfizer. P Casali has been a consultant to Glaxo, Merck SD, PharmaMar, Sanofi Aventis, Novartis and Pfizer and received payment for the development of educational presentations from PharmaMar and Janssen Cilag, and has had travel/accommodation expenses covered or reimbursed by PharmaMar, Novartis and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Wide surgery is the cornerstone of treatment for soft tissue sarcoma (STS). Neoadjuvant/adjuvant radiation therapy decreses local failure in high-risk sarcomas arising from limbs and trunk wall.

• Adjuvant/neoadjuvant combination of anthracycline and ifosfamide has a limited role in localized disease, although it can be discussed in patients with high-risk disease. A study comparing this regimen to all different histological subtypes with a histology-driven approach is presently underway.

• Chemotherapy has been formally approved only as palliation in unresectable/metastatic disease, without showing particular benefit in terms of overall survival.

• Front-line regimens are based on anthracycline alone or in combination with ifosfamide, while conventional second-line agents include high-dose ifosfamide, dacarbazine, gemcitabine + docetaxel.

• Given the variety of histotypes, the choice of second line and sometimes also first-line drugs in metastatic setting is more and more based on the histological subtype: as a matter of fact, taxanes are active in angiosarcoma, gemcitabine alone and/or dacarbazine in leiomyosarcoma, dacarbazine in solitary fibrous tumor, gemcitabine combined to docetaxel in undifferentiated pleomorphic sarcoma, high-dose ifosfamide in synovial sarcoma, trabectedin in liposarcoma and leiomyosarcoma.

• A specific activity of trabectedin, which also targets FUS–CHOP fusion transcript in myxoid/round cell liposarcoma is worthy of note and should always be taken into consideration for this disease.

• Molecular-targeted agents have been recently reported as potentially effective in STS. Some of these have been already largely employed with success in several advanced STS histotypes such as Imatinib in dermatofibrosarcoma protuberans, Pazopanib in nonlipogenic sarcoma, sunitinib in alveolar soft part sarcoma, extraskeletal myxoid chondrosarcoma and solitary fibrous tumors, sorafenib in vascular histologies, while others have recently showed activity in uncommon STS histotypes, such as mTOR inhibitors in perivascular epitheliod cell tumors and cedirinab in alveolar soft part sarcoma.

• While exploiting the activity of new drugs against the activated pathways, immunomodulated target therapies are the next class of agents to test also in sarcomas.