http://repub.eur.nl/res/aut/3012/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/28137/ 2010-01-01T00:00:00Z Background: Adult patients with advanced soft tissue sarcomas (STS) are generally treated similarly, regardless of great differences between STS subtypes, disease presentation and patients' characteristics. As ifosfamide is frequently applied in first line systemic therapy, we aimed to establish prognostic and predictive factors for outcome to ifosfamide-based therapy. Methods: A retrospective, exploratory analysis was performed on data from 1337 advanced STS patients who received first-line ifosfamide-containing chemotherapy. For predictive factor analysis, 660 patients treated with doxorubicin monotherapy served as comparators. Results: Independent favourable prognostic factors for overall survival (OS) were good performance status, female gender, low histological grade, extremity primary tumour site and locally advanced disease; for progression-free survival (PFS), the combination of doxorubicin and ifosfamide, locally advanced disease, and tumour entity with a lower risk to progress for synovial sarcoma patients compared to leiomyosarcoma. For response, independent favourable prognostic factors were doxorubicin combined with ifosfamide, higher histological grade, and histology with synovial sarcoma patients having the highest chance to respond. Predictive factor analysis showed that compared to doxorubicin monotherapy, patients who benefited less from ifosfamide-based therapies were leiomyosarcoma patients in terms of OS, and patients with liposarcoma for response. No predictive factors were found for PFS. Conclusion: In this study, we established an independent set of prognostic and predictive factors for outcome to ifosfamide-based chemotherapy in advanced STS patients. This study provides important information for the interpretation and design of clinical trials for specific STS entities and may contribute to further treatment individualisation of advanced STS patients. http://repub.eur.nl/res/pub/25261/ 2009-07-01T00:00:00Z Lymphopenia is frequent in advanced cancers and predicts the toxicity of chemotherapy. Its effect on relapse and survival is uncertain. Its prognostic value for survival was analyzed in three databases of previously reported prospective multicenter studies: (a) FEC chemotherapy in metastatic breast carcinoma; (b) CYVADIC in advanced soft tissue sarcoma (European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group 62791); and (c) prospective, consecutive phase III studies of aggressive diffuse large-cell non-Hodgkin's lymphomas conducted at Centre Léon Bérard between 1987 and 1993. Univariate and multivariate analyses of prognostic factors for survival were performed. The incidence of lymphopenia of <1,000/μL before treatment was constant among the series: 25%, 24%, and 27%, respectively. Lymphopenia was significantly more frequent (P < 0.05) in metastatic breast cancer patients with performance status (PS) of >1, non-Hodgkin's lymphoma patients with international prognostic index (IPI) of > 0, and advanced soft tissue sarcoma and metastatic breast cancer patients with bone metastases. In univariate analysis, lymphopenia of <1,000/μL significantly correlated to overall survival in patients with metastatic breast cancer (median, 10 versus 14 mo; P < 0.0001), advanced soft tissue sarcoma (median, 5 versus 10 months; P < 0.01), and non-Hodgkin lymphoma (median, 11 versus 94 months; P < 0.0001). In multivariate analysis (Cox model), lymphopenia was an independent prognostic factor for overall survival in metastatic breast cancer [RR (relative risk), 1.8; 95% CI (confidence interval), 1.3-2.4] along with liver metastases and PS; in advanced soft tissue sarcoma (RR, 1.46; 95% CI, 1.0-2.1) along with liver metastases, lung metastases, and PS; and in non-Hodgkin's lymphoma (RR, 1.48; 95% CI, 1.03-2.1) along with IPI. Our findings show that lymphopenia is an independent prognostic factor for overall and progression-free survival in several cancers. http://repub.eur.nl/res/pub/25268/ 2009-06-15T00:00:00Z Purpose: Altered expression of cell cycle/apoptosis key regulators may promote tumor progression, reflect secondary genetic/epigenetic events, and impair the effectiveness of therapy. Their expression pattern might then identify gastrointestinal stromal tumor (GIST) patient subgroups with different response to imatinib and elucidate novel therapeutic targets. Experimental Design: Immunohistochemical evaluation of expression of p53, p16, p21, CHK2, CCND1, BCL2, CDK4, and MDM2 was done on 353 histologically validated GIST patients enrolled into a European/Australasian phase III trial. TP53 was screened for mutations in cases with presumptive nonfunctional protein; that is, high p53 and low expression of the two downstream molecules p21 and MDM2. Results were correlated with clinicopathologic data, KIT/PDGFRA mutation status, and imatinib dosage. Results: Frequent impaired expression was found for BCL2 (78%), CHK2 (53%), p53 (50%), and p16 (47%). Stomach-originating GISTs showed significantly lower expression of p21, p16, and BCL2. KIT/PDGFRA wild-type GISTs had significant lower expression of CDK4. Eighty-eight percent of the high p53 expressers show low downstream target activation, indicating a nonfunctional p53 route. Of these high p53 expressers, 16.4% harbor a detectable TP53 mutation. Multivariate analysis, including previously identified markers, showed an independent effect of p53 and p16 on progression-free survival (PFS). Patients with high level of CHK2 and p21 showed significantly better PFS upon a high-dose regimen. Conclusions: Impaired p53, p16, BCL2, and CHK2 expression is common in advanced GISTs. Distinct patterns of expression correlate with tumor site, genotype, and PFS. Cell cycle/apoptosis maintenance is instrumental for optimal response to imatinib. http://repub.eur.nl/res/pub/30191/ 2008-12-15T00:00:00Z Purpose: Smoking is a potent inducer of cytochrome P450 (CYP) 1A2 and may affect the pharmacokinetics of CYP1A2 metabolized drugs. The effect of smoking on the pharmacokinetics of imatinib, which is metabolized by CYP3A4 and partly by CYP1A2, is unknown. We studied the effect of smoking on imatinib pharmacokinetics, safety, and efficacy. Experimental Design: Imatinib pharmacokinetics, safety, and efficacy was analyzed in 45 patients with gastrointestinal stromal tumors (GIST) or soft-tissue sarcoma included in two European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group trials, including 15 smokers and 30 nonsmokers. Apparent oral clearance, distribution volume, elimination half-life, and dose-standardized area under the concentration curve (AUC) were assessed in 34 patients using nonlinear mixed-effect modeling. Results: Mean ± SD pharmacokinetic variables in smokers (n = 9) versus nonsmokers (n =25) groups were 9.6 ± 5.5 versus 9.2 ± 4.6L/h (apparent oral clearance), 216.5 ± 114.3 versus 207.0 ± 116.9 L (distribution volume), 16.1 ± 6.0 versus 16.5 ± 6.0 h (elimination half-life), and 133.6 ± 71.0 versus 142.3 ± 84.0 ng h/mL mg area under the concentration curve; P > 0.05. Smokers experienced more grade 2/3 anemia (P = 0.010) and fatigue (P = 0.011) and those with GIST had a significantly shorter overall survival (P = 0.037) and time to progression (P = 0.052). Conclusions: This retrospective study suggests that the pharmacokinetics of imatinib is not affected by smoking. However, smokers have an increased risk of anemia and fatigue. Smokers with GIST have a shorter overall survival and time to progression. http://repub.eur.nl/res/pub/14488/ 2008-11-01T00:00:00Z Rationale: Angiosarcomas of soft tissue represent a heterogenous group of rare sarcomas with specific clinical behaviour and risk factors. Paclitaxel appears to induce tumour control in a higher proportion of patients with angiosarcoma, as compared to other sarcomas. The objective of this retrospective study was to assess the anti-tumour activity of this compound in a multicentre setting. Method: Clinical data from patients with angiosarcomas of soft tissue treated with single agent paclitaxel were collected from the centres of the soft tissue and bone sarcoma group of EORTC, using a standardised data collection form. Paclitaxel could be given every three weeks, or weekly. Statistical analysis was performed using SAS software. Results: Data from 32 patients were collected from 10 centres. There were 17 males, 15 females, with a median age of 60.4 years (range, 25-91). Primary angiosarcomas were located in scalp and face in 8 patients (25%) and at other primary sites in 24 patients (75%). All patients had intermediate (n = 13) or high grade (n = 19) primary tumours. Thirteen (40%) patients had been pretreated with doxorubicin-based first-line-chemotherapy and three of them (9%) had also received second-line chemotherapy with ifosfamide. Eleven (34%) patients had been irradiated before as treatment for angiosarcoma. In 8 (25%) patients, the angiosarcoma occurred at sites of prior radiation therapy for other malignancies. The response rate was 62% (21/32) in the whole series, 75% (6/8) in scalp angiosarcomas and 58% (14/24) in other primary sites. The median time to progression was 7.6 months (range, 1-42) for the whole group. For the face/scalp group it was 9.5 months, and for patients with angiosarcomas at other sites it was 7.0 months, respectively. Conclusion: Paclitaxel was found to be an active agent in angiosarcoma of soft tissue in this retrospective analysis. These results need to be confirmed in a prospective randomised phase II study. http://repub.eur.nl/res/pub/15252/ 2008-09-01T00:00:00Z Rationale: The 62005 EORTC phase III trial, comparing two doses of imatinib in patients with advanced GIST, reported a median progression-free survival of 25 months with a trend towards dose dependency for progression-free survival. The current analysis of that study aimed to assess whether histological/immunohistochemical parameters correlate with clinical response to imatinib. Patients and methods: Pre-treatment samples of GISTs from 546 patients enroled in phase III study were analysed for immunohistochemical characteristics, correlations with clinicopathological data, with survival and with tumours' genotype. Results: There was no correlation between immunomorphological or clinical characteristics and response to treatment, PFS or OS. No correlations between immunophenotype of the tumour and PFS or OS in the two dose arms were observed. Conclusions: The results confirm the heterogeneity of GIST in terms of immunophenotypic expression, but indicate that these parameters have no impact on the outcome of the patients under imatinib treatment. http://repub.eur.nl/res/pub/36488/ 2007-04-01T00:00:00Z Recent publications have suggested that imatinib (Glivec) may be cardiotoxic. We have therefore assessed the largest study on the agent performed in patients with gastrointestinal stromal tumours, randomising a daily dose of 400 mg versus 800 mg. 946 Patients were entered, 942 patients received at least one dose of imatinib. The median time on treatment was 24 months. A total of 24,574 exposure months could be analysed. We could not identify an excess of cardiac events in the study population. In 2 patients (0.2%) a possible cardiotoxic effect of imatinib could not fully be excluded. The current analysis of a large randomised prospective study could not confirm previous suggestions of imatinib induced cardiac toxicity. http://repub.eur.nl/res/pub/36535/ 2007-01-01T00:00:00Z The study aimed to assess the efficacy and safety of brostallicin, a new DNA minor groove binder, at a dose of 10 mg/m2, intravenous (i.v.) every three weeks, in patients with advanced or inoperable soft tissue sarcoma (STS) and gastrointestinal stromal tumour (GIST) failing first line therapy. Two groups were recruited: (1) GIST following treatment with imatinib; (2) other STS following treatment with single agent doxorubicin or ifosfamide or a single line of combination therapy. The primary end-point was overall response rate (ORR) as defined by response evaluation criteria in solid tumours (RECIST). Progression free survival (PFS) was a secondary end-point. In the GIST group, a Simon two step design was planned: first step 18 patients, total 32 patients (p1 = 20% p0 = 5% alpha = beta = 0.1). In the non-GIST group, planned sample size was 40 in a standard Fleming one-step design (p0 = 10%, p1 = 25%, alpha = beta = 0.1). Forty-three patients with non-GIST and 21 patients with GIST were recruited. In general, the drug was well tolerated. Common Toxicity Criteria (CTC) grade 3 or grade 4 toxicity was granulocytopenia: 70% of patients, 50% of cycles; fatigue: 25% of patients, 8% of cycles; febrile neutropenia: 14% of patients, 4% of cycles. There was one confirmed toxic death due to neutropenic septicaemia. Three patients had clinically significant allergic reactions in 249 cycles delivered. In the GIST group, no patients had a confirmed response and recruitment was discontinued at the first step. In the non-GIST group, there were two confirmed partial responses. The 3 month PFS was 46% in the non-GIST group and 33% in the GIST group. In the non-GIST group, this PFS is in the range of other agents considered active in STS, and may predict for more substantial first line activity. Further investigation in STS other than GIST appears warranted. http://repub.eur.nl/res/pub/7811/ 2006-06-08T00:00:00Z A general description of soft tissue sarcomas and their treatments is given in Chapter 1. The chapter also provides an introduction to the work on prognostic factors that is described in this thesis. In chapter 2, we have identified the characteristics of the patients (and of their disease) influencing the survival expectation and the probability to respond to first line chemotherapy for advanced disease. Not surprisingly, advanced age is an adverse prognostic factor of survival and response to therapy. Poor performance adversely affects survival but not the probability of response to first line therapy. The number and size of the lesions does not affect response and neither survival, at the time of diagnosis of advanced disease. The survival prognosis is more favorable if the sarcoma was diagnosed at least 2 years before chemotherapy was needed. Patients who were initially diagnosed with low grade disease have a longer survival expectation, despite the fact that they respond less frequently to chemotherapy; and they are probably not appropriate candidates to test the activity of new drugs, especially if response is used as principal end-point.