Predictors for doxorubicin-induced hematological toxicity and its association with outcome in advanced soft tissue sarcoma patients; a retrospective analysis of the EORTC-soft tissue and bone sarcoma group database

Introduction: As both anti-tumour effects and toxicity are thought to be dose-dependent, patients with the greatest toxicity may also have the best outcome. We assessed whether severity of doxorubicin-induced hematological toxicity is associated with outcome in advanced soft tissue sarcoma (STS) patients. In addition, risk factors for hematological toxicity were explored. Methods: Worst haematological toxicities (anaemia, leukopenia, neutropenia and thrombocytopenia) seen during treatment were scored according to CTCAE toxicity score. Differences in overall survival (OS), progression free survival (PFS) and response rate (RR) between patients with or without high haematological toxicity (grades 0–2 vs. 3–4) were assessed using conventional statistical tests. Associations between baseline characteristics and hematological toxicity were established using logistic multivariate regression. Results: In 557 patients eligible for this analysis, 47.2% of the patients received at least six cycles of treatment; 45% stopped treatment early due to progression, 3% because of toxicity. Relative dose intensity (RDI) was constant over the cycles. OS, PFS, and RR did not differ between patients with grade 3/4 toxicity during treatment versus those with grade 1/2. Risk factors for grade 3/4 haematological toxicity, in particular neutropenia, were age above 60 years, low BMI, and female gender. Conclusion: In this large series, risk factors for haematological toxicity in STS patients receiving doxorubicin monotherapy were revealed. The finding that there was no association between outcome and haematological toxicity during doxorubicin treatment may be useful to reassure advanced STS patients that failure to experience haematological toxicity during treatment does not equate to under-treatment

An update on the management of sporadic desmoid-type fibromatosis: A European Consensus Initiative between Sarcoma PAtients EuroNet (SPAEN) and European Organization for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group (STBSG)

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

Final analysis of the randomized trial on imatinib as an adjuvant in localized gastrointestinal stromal tumors (GIST) from the EORTC Soft Tissue and Bone Sarcoma Group (STBSG), the Australasian Gastro-Intestinal Trials Group (AGITG), UNICANCER, French Sarcoma Group (FSG), Italian Sarcoma Group (AGITG), UNICANCER, French Sarcoma Group (FSG), Italian Sarcoma Group (ISG), and Spanish Group for Research on Sarcomas (GEIS)

Background: 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.Patients and methods: 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.Results: 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.Conclusions: 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.Experimentele farmacotherapi

Pazopanib for metastatic sarcoma: author's reply

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Pazopanib in advanced desmoplastic small round cell tumours: a multi-institutional experience

Contains fulltext : 136490.pdf (publisher's version ) (Open Access)BACKGROUND: We retrospectively reviewed data from nine pre-treated metastatic desmoplastic small round cell tumour (DSRCT) patients who received pazopanib. PATIENTS AND METHODS: Three patients received pazopanib within the EORTC phase II 62043, three in the EORTC phase III 62072, and three in the context of UK named patient program. RESULTS: Nine patients were retrieved from the databases, the median age was 30 years (range: 21-47), they were all males. All had received prior chemotherapy. At the time of treatment start, 4 patients (44%) had ECOG PS 0, 4 (44%) PS 1, 1 (11%) PS 2. Best response was partial response (PR) in 2/9 (22%) patients, stable disease (SD) in 5/9 (56%) and progressive disease (PD) in 2/9 (22%) with a clinical benefit rate (PR + SD > 12 weeks) of 78%. Median PFS and OS were 9.2 (95%CI: 0-23.2) and 15.4 (95%CI: 1.5-29.3) months respectively. With a median follow-up of 20 months, 2/9 (22%) patients are still alive, all progressed. The most common toxicities included neutropenia (G1-2 45%; G3-4 11%), anaemia (G1-2 45%), fatigue (G1-2 67%), diarrhoea (G1-2 45%; G3-4 11%), nausea (G1-2 45%), hypertension (G1-2 45%) and increase in liver enzymes (G1-2 34%; G3-4 11%). Three patients (34%) required a dose reduction. One of the patients discontinued treatment because of persistent increase in total bilirubin level, one due to patient's choice. CONCLUSION: In this series, pazopanib showed interesting activity in DSRCT patients who progressed after prior chemotherapy without major toxicity

Predictors for doxorubicin-induced hematological toxicity and its association with outcome in advanced soft tissue sarcoma patients; a retrospective analysis of the EORTC-soft tissue and bone sarcoma group database

Contains fulltext : 196658.pdf (publisher's version ) (Open Access)INTRODUCTION: As both anti-tumour effects and toxicity are thought to be dose-dependent, patients with the greatest toxicity may also have the best outcome. We assessed whether severity of doxorubicin-induced hematological toxicity is associated with outcome in advanced soft tissue sarcoma (STS) patients. In addition, risk factors for hematological toxicity were explored. METHODS: Worst haematological toxicities (anaemia, leukopenia, neutropenia and thrombocytopenia) seen during treatment were scored according to CTCAE toxicity score. Differences in overall survival (OS), progression free survival (PFS) and response rate (RR) between patients with or without high haematological toxicity (grades 0-2 vs. 3-4) were assessed using conventional statistical tests. Associations between baseline characteristics and hematological toxicity were established using logistic multivariate regression. RESULTS: In 557 patients eligible for this analysis, 47.2% of the patients received at least six cycles of treatment; 45% stopped treatment early due to progression, 3% because of toxicity. Relative dose intensity (RDI) was constant over the cycles. OS, PFS, and RR did not differ between patients with grade 3/4 toxicity during treatment versus those with grade 1/2. Risk factors for grade 3/4 haematological toxicity, in particular neutropenia, were age above 60 years, low BMI, and female gender. CONCLUSION: In this large series, risk factors for haematological toxicity in STS patients receiving doxorubicin monotherapy were revealed. The finding that there was no association between outcome and haematological toxicity during doxorubicin treatment may be useful to reassure advanced STS patients that failure to experience haematological toxicity during treatment does not equate to under-treatment

First-line chemotherapy in advanced intrabdominal well-differentiated/dedifferentiated liposarcoma: An EORTC Soft Tissue and Bone Sarcoma Group retrospective analysis

BACKGROUND No prospective trial with anthracycline-based chemotherapy has individually assessed response in a well-differentiated (WD)/dedifferentiated (DD) liposarcoma patient cohort. We conducted a retrospective analysis of first-line chemotherapy in liposarcoma of intra-abdominal origin (IA-LPS) in patients who had entered the European Organisation for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group (STBSG) trials. METHODS We searched for all adult patients treated with first-line chemotherapy for advanced IA-LPS in the EORTC STBSG phase 2 and 3 trials from 1978. Treatment was aggregated into 5 groups: anthracycline alone, ifosfamide alone, doxorubicin plus ifosfamide (D+IFO), doxorubicin/cyclophosphamide/vincristine/dacarbazine, and "other" (brostallicin, trabectedin). Response was assessed prospectively by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. RESULTS A total of 109 patients with IA-LPS from 13 trials were identified (104 evaluable for response). Overall, there were 10/109 (9.2%) responders: 3/48 (6.3%) in the anthracycline alone group, 2/15 (13%) in the ifosfamide alone group, and 4/18 (22%) in the D+IFO group. At the 10-month median follow-up (interquartile range, 6-24), the median OS was 19 months (95% CI, 15-21) and median PFS 4 months (95% CI, 3-6). D+IFO achieved a not statistically significant longer median PFS (12 months) and median OS (31 months) than observed with other regimens. Univariate/multivariate analysis did not identify prognostic factors. CONCLUSIONS Cytotoxic chemotherapy, in particular anthracycline alone, had marginal activity in advanced IA-LPS. Ifosfamide-containing regimens showed higher activity, although it was not statistically significant and in a small number of cases, with the combination of doxorubicin and ifosfamide appearing to be the more active regimen available in fit patients. This series provides a benchmark for future trials on new drugs in WD/DD liposarcoma