Bad to the Bone: Emerging Approaches to Aggressive Bone Sarcomas

Abstract

Bone sarcomas are rare heterogeneous tumors that affect patients of all ages including children, adolescent young adults, and older adults. They include many aggressive subtypes and patient groups with poor outcomes, poor access to clinical trials, and lack of defined standard therapeutic strategies. Conventional chondrosarcoma remains a surgical disease, with no defined role for cytotoxic therapy and no approved targeted systemic therapies. Here, we discuss promising novel targets and strategies undergoing evaluation in clinical trials. Multiagent chemotherapy has greatly improved outcomes for patients with Ewing sarcoma (ES) and osteosarcoma, but management of those with high-risk or recurrent disease remains challenging and controversial. We describe the impact of international collaborative trials, such as the rEECur study, that aim to define optimal treatment strategies for those with recurrent, refractory ES, and evidence for high-dose chemotherapy with stem-cell support. We also discuss current and emerging strategies for other small round cell sarcomas, such as CIC-rearranged, BCOR-rearranged tumors, and the evaluation of emerging novel therapeutics and trial designs that may offer a new paradigm to improve survival in these aggressive tumors with notoriously bad (to the bone) outcomes.

Ewing Sarcoma of the Female Genital Tract

“…We describe the largest series to date of 21 Ewing sarcoma primary to the gynecologic tract, 20 of which were confirmed via molecular studies. While its behavior and prognosis appear comparable stage for stage to those of its intraosseous and soft tissue counterparts, 11,13 the emphasis herein lies on both the unusual clinical presentations along with histologic and immunophenotypic features, which can mimic other more provincial Müllerian neoplasms.…”

“…[6][7][8][9][10][11][12] A neoplasm of both enigmatic derivation and cellular lineage, the prognosis of Ewing sarcoma is still dependent largely upon the extent of disease at presentation, with larger and metastatic tumors associated with poorer survival despite the development of more powerful therapeutic regimens. 13,14 Not only has our characterization of its underlying pathophysiology and biology evolved significantly in the century since those preliminary observations, but importantly the anatomic distribution has expanded to include more rare extraosseous soft tissue, cutaneous, and visceral sites. 15 As the prototypical "small round blue cell tumor," Ewing sarcoma is frequently included in the differential diagnosis of primitive malignancies of any location in young patients, along with a multitude of other histotypes including germ cell tumors, leukemia, neuroblastoma, rhabdomyosarcoma, and desmoplastic small round cell tumor.…”

Mesenchymal Chondrosarcoma from Diagnosis to Clinical Trials

“…It was reported that adjuvant anthracycline-based chemotherapy for MSC is associated with a significant reduction in recurrence and death. The consensus of sarcoma experts is to use Ewing sarcoma–like treatment regimens in MSC, although no randomized trial has been performed to confirm this approach [ 103 ]. MSC systemic treatment therefore generally includes alternating cycles of etoposide plus ifosfamide (EI) and adriamycin with vincristine and cyclophosphamide (CAV) [ 93 ].…”

Emerging Treatments Targeting the Tumor Microenvironment for Advanced Chondrosarcoma

“…This provided the rationale for developing new drugs, such as inhibitors of tyrosine kinase, activating mutated genes, mammalian target of rapamycin (mTOR), or histone deacetylase (HDAC) [ 37 ] ( Figure 1 ). Unfortunately, most of them, including Hedgehog inhibitors that elicited good pre-clinical responses, failed to demonstrate a survival benefit when translated into clinical trials [ 38 ]. Although recent studies have demonstrated good short-term results after intralesional surgical procedures for low-grade ChSs treated with curettage and adjuvant treatments consisting of phenol application, cauterization, or cryotherapy, the primary and preferred treatment for ChS patients with localized disease remains radical surgical resection with wide margins [ 27 , 39 , 40 , 41 ].…”