Soft tissue sarcomas are rare cancers but because of their association with characteristic chromosomal translocations and activating mutations they may be particularly susceptible to molecularly ...targeted therapies. Gastrointestinal stromal tumour (GIST) became the paradigm for targeted therapy in solid tumours owing to the success of imatinib, which has transformed the prognosis in this disease. Translocation-driven tumours have proved harder to target, but the impact of fusion proteins on gene expression is beginning to be understood and may also reveal new targets for therapy, such as insulin-like growth factor 1 receptor, now that effective inhibitors have been discovered. Angiogenesis inhibition also appears to be a promising area for research in sarcomas and many new targets are emerging at the same time as agents capable of investigating them in the clinic are being developed. It is not unrealistic to hope that targeted therapies will play an increasing role in the management of sarcomas in the near future.
Desmoid-type fibromatosis is a rare and locally aggressive monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Currently, there is no ...established or evidence-based treatment approach available for this disease. Therefore, in 2015 the European Desmoid Working Group published a position paper giving recommendations on the treatment of this intriguing disease. Here, we present an update of this consensus approach based on professionals’ AND patients’ expertise following a round table meeting bringing together sarcoma experts from the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group with patients and patient advocates from Sarcoma PAtients EuroNet. In this paper, we focus on new findings regarding the prognostic value of mutational analysis in desmoid-type fibromatosis patients and new systemic treatment options.
In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery in localized, high/intermediate-risk gastrointestinal stromal tumors (GIST) ...patients. Interim analysis results were published in 2015 upon recommendation from an independent data review committee. We report the final outcome of the study.
This was a randomized, open-label, multicenter phase III trial carried out at 112 hospitals in 12 countries. Patients were randomized to 2 years of imatinib, 400 mg daily, or no further therapy after surgery. The primary endpoint was imatinib failure-free survival (IFFS), while relapse-free survival (RFS), relapse-free interval (RFI), overall survival (OS) and toxicity were secondary endpoints. Adjusting for the interim analyses, results on IFFS were assessed on a 4.3% significance level; for the other endpoints, 5% was used.
Nine hundred and eight patients were randomized between January 2005 and October 2008: 454 to imatinib and 454 to observation; 835 patients were eligible. With a median follow-up of 9.1 years, 5 (10)-year IFFS was 87% (75%) in the imatinib arm versus 83% (74%) in the control arm hazard ratio (HR) = 0.87, 95.7% confidence interval (CI) (0.65; 1.15), P = 0.31; RFS was 70% versus 63% at 5 years and 63% versus 61% at 10 years, HR = 0.71, 95% CI (0.57; 0.89), P = 0.002; OS was 93% versus 92% at 5 years and 80% versus 78% at 10 years HR = 0.88, 95% CI (0.65; 1.21), P = 0.43. Among 526 patients with high-risk GIST by local pathology, 10-year IFFS and RFS were 69% versus 61%, and 48% versus 43%, respectively.
With 9.1 years of follow-up, a trend toward better long-term IFFS in imatinib-treated patients was observed in the high-risk subgroup. Although the difference was not statistically significant and the surrogacy value of such an endpoint is not validated, this may be seen as supporting the results reported by the Scandinavian/German trial, showing a sustained small but significant long-term OS benefit in high-risk GIST patients treated with 3 years of adjuvant imatinib.
•Adjuvant imatinib for 2 years significantly improved RFS, with a trend towards a better imatinib failure free survival.
Aims: Key prognostic factors at diagnosis of synovial sarcoma are well defined from the literature. There are few data regarding prognostic parameters in the setting of advanced disease. Our aim was ...to look specifically at a cohort of patients with advanced synovial sarcoma and to identify potential prognostic factors. Patients and methods: One hundred and four patients with advanced synovial sarcoma were identified from the Royal Marsden Hospital's sarcoma database between 1978 and 2003. Patient data were analysed retrospectively. Most patients were aged between 20 and 50 years at diagnosis. Seventy-one patients were deceased at the time of analysis. Ninety-two patients received chemotherapy for management of advanced disease (most commonly doxorubicin + ifosfamide). Results: Median survival following development of advanced disease was 22 months. Predictors of survival with advanced disease were age <35 years (P=0.03) and response to first-line chemotherapy (P=0.05). The response rate to doxorubicin plus ifosfamide was 58.6%, and this was superior to either agent when given singly. Metastasectomy was not associated with improved prognosis in this series. Conclusions: Synovial sarcoma is a chemosensitive soft tissue sarcoma. Compared with historical controls, survival with advanced disease seems to have improved over the years, possibly as a result of better use of chemotherapy. Age <35 years and response to first-line chemotherapy predict for improved survival with advanced disease.
Imatinib, a selective tyrosine kinase inhibitor, is currently the standard of care first-line treatment for unresectable or metastatic gastrointestinal stromal tumour (GIST), improving survival time ...and delaying disease progression in many patients. Nevertheless, primary and secondary (acquired) resistance to imatinib is a substantial problem in routine clinical practice. Sunitinib is an oral, multitargeted tyrosine kinase inhibitor that was approved for the treatment of imatinib-resistant or -intolerant GIST. In the pivotal phase III study, sunitinib provided substantial clinical benefits including disease control and superior survival versus placebo as second-line treatment. Treatment with sunitinib was reasonably well tolerated. The availability of sunitinib represents an important clinical advance in GIST management, providing physicians and patients with an effective therapy when resistance to imatinib develops.
Vascular and angiogenic processes provide an important target for novel cancer therapeutics. Dynamic contrast-enhanced magnetic resonance imaging is being used increasingly to noninvasively monitor ...the action of these therapeutics in early-stage clinical trials. This publication reports the outcome of a workshop that considered the methodology and design of magnetic resonance studies, recommending how this new tool might best be used.
We have estimated progression-free rates (PFR) for various groups of soft-tissue sarcoma patients from our clinical trials database, to provide reference values for conducting phase II studies with ...PFR as the principal end-point. In 146 pretreated patients receiving an active agent, the PFR estimates were 39 and 14% at 3 and 6 months; with inactive regimens (234 patients), those estimates were 21 and 8% respectively. In 1154-non-pretreated patients, PFR estimates varied from 77% (synovial sarcoma) to 57% (malignant fibrous histiocytoma (MFH)) at 3 months, and from 56% (synovial sarcoma) to 38% (MFH) at 6 months. In 61 leiomyosarcomas from gastrointestinal origin, the corresponding figures were 44 and 30%, respectively. Consequently, for first-line therapy, a 6-month PFR of ⩾30–56% (depending on histology) can be considered as a reference value to suggest drug activity; for second-line therapy, a 3-month PFR of ⩾40% would suggest a drug activity, and ⩽20% would suggest inactivity.
The characterisation and clinical relevance of tumour-infiltrating lymphocytes (TILs) in leiomyosarcoma (LMS), a subtype of soft tissue sarcoma that exhibits histological heterogeneity, is not ...established. The use of tissue microarrays (TMA) in studies that profile TIL burden is attractive but given the potential for intra-tumoural heterogeneity to introduce sampling errors, the adequacy of this approach is undetermined. In this study, we assessed the histological inter- and intra-tumoural heterogeneity in TIL burden within a retrospective cohort of primary LMS specimens. Using a virtual TMA approach, we also analysed the optimal number of TMA cores required to provide an accurate representation of TIL burden in a full tissue section. We establish that LMS have generally low and spatially homogenous TIL burdens, although a small proportion exhibit higher levels and more heterogeneous distribution of TILs. We show that a conventional and practical number (e.g. ≤3) of TMA cores is adequate for correct ordinal categorisation of tumours with high or low TIL burden, but that many more cores (≥11) are required to accurately estimate absolute TIL numbers. Our findings provide a benchmark for the design of future studies aiming to define the clinical relevance of the immune microenvironments of LMS and other sarcoma subtypes.
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