Current PerspectiveFuture treatment of soft tissue sarcomas will be driven by histological subtype and molecular abberations
Introduction
Soft tissue sarcomas are a rare group of diseases that all together comprise only 1% of all malignancies. Because of their relative rarity, soft tissue sarcomas have up to now been grouped certainly for the purpose of assessing treatment outcome in practice as well as in prospective clinical studies exploring drug treatment.
In the analyses of the large database of EORTC on sarcomas, histological subtype (with possible exception of very rare histological subtypes such as clear cell sarcoma and alveolar soft part sarcoma the numbers of which were extremely small in this large database) could not be identified as an important prognostic factor of response to either doxorubicin of ifosfamide-based cytotoxic therapy, independent of other clinical factors.1, 2 Yet the analysis of 3- and 6-month progression-free rates after first line drug treatment for metastatic disease from the EORTC database suggested differences in results between subtypes.3 In addition to these data, increasing number of reports, not least related to our increasing knowledge of molecular biology of these diseases, have suggested that the various subtypes of soft tissue sarcomas should be approached individually.4 While the latter may be an obvious thought for drugs targeted against specific molecular aberrations in cancer cells, it may be less obvious for cytotoxic drugs, which are commonly thought to be less cancer-specific. Yet the literature is filling up with evidence that even for cytotoxic drugs the assumption holds.
In this paper we will first review the data on increased sensitivity of specific subtypes of soft tissue sarcomas to specific cytotoxic agents, summarise in brief the current status for molecular targeted agents, and finally discuss the findings in light of the need for adapting our clinical trial designs.
Section snippets
Cytotoxic agents
There are only two agents that have been considered active in soft tissue sarcomas in general, Doxorubicin and Ifosfamide.1, 2 In the above-mentioned analyses of the EORTC database on more than 2500 patients treated with doxorubicin1 and over 1700 patients treated with ifosfamide-based therapy,2 there was no distinct histological subtype that emerged as more sensitive to these agents. Currently, for the treatment of soft tissue sarcomas in general, doxorubicin cannot be favoured over ifosfamide
Gastrointestinal stroma tumours (GISTs)
The development of Imatinib for GIST serves as an example for the development of treatment based on cancer (cell)-specific molecular changes. Overexpression of the oncogene product receptor c-KIT (CD117) is a frequent, albeit not specific, characteristic of GIST. Importantly, this receptor is known to frequently harbour activating mutations in GIST.33, 34 The activity of the KIT-tyrosine kinase inhibitor imatinib was clearly shown.35, 36, 37, 38 Detailed analysis has now revealed that Exon 9
Study design
Collectively these data suggest that soft tissue sarcomas should preferably no longer simply be pooled together in clinical studies. Not from a pathology point of view, and not from a molecular abnormality point of view. For instance, Chugh et al62 performed an interesting phase II study on imatinib in 190 soft tissue sarcomas. They used a Bayesian Hierarchical Statistical Model (BHM), and borrowed information across sarcoma subtypes assuming that they were interrelated in expression of
Conclusion
The development of Imatinib for GIST has clearly the hallmark of molecular-change-specific treatment in sarcomas. However, our experience with inhibiting KIT has also taught us that simply chasing a target without fully understanding its functionality for tumour growth will lead to disappointment.
Positively, recent research on the molecular biology of soft tissue sarcomas has identified several possible targets for drug development in specific sarcoma subtypes or even shared among various
Conflict of Interest
No Conflict of Interest.
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