Comprehensive analysis of published phase I/II clinical trials between 1990-2010 in osteosarcoma and Ewing sarcoma confirms limited outcomes and need for translational investment

Abstract

BackgroundHigh grade primary bone sarcomas are rare cancers that affect mostly children and young adults. Osteosarcoma and Ewing sarcoma are the most common histological subtypes in this age group, with current multimodality treatment strategies achieving 55-70% overall survival. As there remains an urgent need to develop new therapeutic interventions, we have reviewed published phase I/II trials that have been reported for osteosarcoma and Ewing sarcoma in the last twenty years.ResultsWe conducted a literature search for clinical trials between 1990 and 2010, either for trials enrolling bone sarcoma patients as part of a general sarcoma indication or trials specifically in osteosarcoma and Ewing sarcoma. We identified 42 clinical trials that fulfilled our search criteria for general sarcoma that enrolled these patient groups, and eight and twenty specific trials for Ewing and osteosarcoma patients, respectively. For the phase I trials which enrolled different tumour types our results were incomplete, because the sarcoma patients were not mentioned in the PubMed abstract. A total of 3,736 sarcoma patients were included in these trials over this period, 1,114 for osteosarcoma and 1,263 for Ewing sarcoma. As a proportion of the worldwide disease burden over this period, these numbers reflect a very small percentage of the potential patient recruitment, approximately 0.6% for Ewing sarcoma and 0.2% for osteosarcoma. However, these data show an increase in recent activity overall and suggest there is still much room for improvement in the current trial development structures.ConclusionLack of resources and commercial investment will inevitably limit opportunity to develop sufficiently rapid improvements in clinical outcomes. International collaboration exists in many well founded co-operative groups for phase III trials, but progress may be more effective if there were also more investment of molecular and translational research into disease focused phase I/II clinical trials. Examples of new models for early translational and early phase trial collaboration include the European based EuroBoNeT network, the Sarcoma Alliance for Research through Collaboration network (SARC) and the new European collaborative translational trial network, EuroSarc.

A Review of Targeted Therapies Evaluated by the Pediatric Preclinical Testing Program for Osteosarcoma

“…Over the last decade, technological advances in research and medicine have provided detailed descriptions of factors that contribute to the malignant phenotype of this disease with the hope of finding new therapeutic treatments and strategies. The recent review of van Maldegem et al (2012) of published clinical trials for OS shows that most phase III trials are combination treatments of conventional chemotherapy agents. Many biological based treatments evaluated in the PPTP and phase I and II trials have yet to advance to phase III trials.…”

Synergistic Effects of a Smac Mimetic with Doxorubicin Against Human Osteosarcoma

“…Substantial improvements in surgery and chemotherapy have increased the survival rate of patients with localized disease. However, the prognosis of patients with metastatic or recurrent disease is still poor owing to the lack of second-line chemotherapies (4)(5)(6). This necessitates the development of better and safer chemotherapeutic strategies against osteosarcomas.…”

AICAR induces mitochondrial apoptosis in human osteosarcoma cells through an AMPK-dependent pathway

“…Many studies have reported significant advances in adjuvant chemotherapy for osteosarcoma (1,2), however, in the last two decades, treatment outcomes for patients with osteosarcoma have not improved sufficiently, despite the implementation of several new therapeutic interventions. In a comprehensive analysis of published phase I/II clinical trials, researchers found that effective drugs tended to have high toxicity (3). Therefore, new therapeutic strategies for the treatment of osteosarcoma are needed.…”