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Cut to the chase: on the need for genotype-specific soft tissue sarcoma trials.

Human cancers are defined by mutations irrespective of their tissue of origin, and knowledge of the functional effects of these mutations is rapidly changing the way we clinically manage patients. In retrospect, it could be argued that the persistent use of an anatomical-based classification of human tumours, as opposed to a molecular classification, has been a major impediment to our progress in treating these diseases. To some extent, this has been exemplified by the grouping of ‘sarcoma’ tumours to those arising from bone and soft tissues. Despite the World Health Organisation-based reclassification of soft tissue sarcoma into at least 60 separate types based on very strong genotype–phenotype data, the clinical management of soft tissue tumours has until recently remained a combination of surgical excision, radiotherapy and chemotherapy. There are important key clinical elements to these modalities that form the mainstay of our current and future treatment strategies, for example resection margin and radiotherapy dose, and these are unlikely to change. However, there are also practices we must be prepared to change and if appropriate discard. One of these is the empirical use of adjuvant high-dose combination chemotherapy in completely resected adult soft tissue sarcoma. In both osteosarcoma and Ewing’s-like bone sarcomas, neoadjuvant combination chemotherapy and assessment of tumour histological response are well-advanced approaches currently being tested in large phase III trials. In both circumstances, the empirical adoption of dose-intensive chemotherapy appears to have improved diseasefree survival (DFS) and clinical outcome, despite the different molecular aetiologies of these sarcoma types. In both these circumstances, the tumours are sufficiently common and homogenous at the molecular level (e.g. Ewing Sarcoma breakpoint region 1-based fusion genes) and are frequent enough to warrant development of separate international phase III trials (EUROEWINGS-99 and EURAMOS-1) [2, 3]. Similar approaches in specific soft tissue sarcoma genotypes have been less successful, partly because of the relative rarity of each type. Both a meta-analysis and a preliminary combined trial report of adjuvant ifosfamide and doxorubicin [European Organisation for Research and Treatment of Cancer (EORTC) 62931, n = 351] and CYVADIC (EORTC 62771, n = 468) have failed to detect any significant overall survival (OS) benefit, even though there may be a small effect on prolongation of DFS in some subgroups [4, 5]. Aside from the prolonged duration to recruit to these studies (up to 9 years), there were a number of observations and confounding factors with these trials. The first was the huge importance of resection margin over any other variable, even with the potential for improved benefit of adjuvant chemotherapy in R1 (macroscopically clear, but microscopically involved) versus R0 resection (macroand microscopically clear). The second was the dose of combination chemotherapy, as ifosfamide dose response appears to exist at least in advanced disease and it may be equally important in the adjuvant setting [6]. The third was the observation that males of all ages and patients over 40 years appeared to have an improved OS as subgroups. Fourth, and probably the most important issue, was the issue of sarcoma genotype. Even in the combined analysis, the 108 patients with synovial sarcoma showed no improved OS compared with the other sarcoma histological subtypes [5]. For any oncologic intervention, disease uniformity within the patient group to be studied is a variable that must be quantified and carefully controlled for in order to ensure an accurate appraisal of any intervention in that specific group. By definition, soft tissue sarcoma trials have generally failed to do this, mainly because of a combination of reasons that include the rarity of the diagnosis, the use of soft tissue sarcoma as a pragmatic definition in order to facilitate trial recruitment and the lack of targeted disease-specific therapies. With this basis, Italiano et al. [1] in this issue have retrospectively analysed the outcome of synovial sarcoma adjuvant treatment in France. Why synovial sarcoma? First, the disease has consistent genotypic abnormalities, chromosomal translocations generating fusion proteins, SS18(SYT)-SSX1, SS18(SYT)-SSX2 or SS18(SYT)-SSX4, that result in a surprisingly mixed histological picture of mesenchymal as well as epithelial morphology, referred to as monoand biphasic, respectively [7–9]. Secondly, this sarcoma is relatively common ( 10% of soft tissue sarcoma) and thirdly, because it has a high response rate to ifosfamide-based chemotherapy ( 50%) [10]. This latter point is important, for if there was no benefit of adjuvant chemotherapy detected in synovial sarcoma, then the use of adjuvant ifosfamide-based chemotherapy in other forms of soft tissue sarcoma would be extremely unlikely to be of benefit. In a nonrandomised retrospective analysis of 157 synovial sarcoma cases that received neoadjuvant and adjuvant chemotherapy (60% with ifosfamide), no improvement in DFS was detected. This result confirmed the combined randomised trial analysis [5]. For radiotherapy, local disease control was improved as expected and resection margin again dominated the picture. A separate retrospective analysis of a further 255 patients has also led to the development of a nomogram that suggested a subtle improvement in disease-specific survival in the first 3 years after doxorubicin and ifosfamide combination e d it o ri a l