UZ Leuven

European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Donato di Paola E, Dimitrijevic S, Martens M, Webb A, Sciot R, Van Glabbeke M, Silberman S, Nielsen OS.  Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 2001;358(9291):1421-3. Abstract: Background Gastrointestinal stromal tumours (GISTs) are rare tumours of the gastrointestinal tract characterised by cell-surface expression of the tyrosine kinase KIT(CD117). No effective systemic treatment is available. Imatinib (ST1571) inhibits a similar tyrosine kinase, BCR-ABL, leading to responses in chronic myeloid leukaemia, and has also been shown to inhibit KIT. We did a phase I study to identify the dose-limiting toxic effects of imatinib in patients with advanced soft tissue sarcomas including GISTs. Methods 40 patients (of whom 36 had GISTs) received imatinib at doses of 400 mg once daily, 300 mg twice daily, 400 mg twice daily, or 500 mg twice dally. Toxic effects and haematological, biochemical, and radiological measurements were assessed during 8 weeks of follow-up. (18)Fluorodeoxyglucose positron-e mission tomography (PET) was used for response assessment in one centre. Findings Five patients on 500 mg imatinib twice daily had dose-limiting toxic effects (severe nausea, vomiting, oedema, or rash). Inhibition of tumour growth was seen in all but four patients with GISTs, resulting in 19 confirmed partial responses and six as yet unconfirmed partial responses or more than 20% regressions. 24 of 27 clinically symptomatic patients showed improvement, and 29 of 36 were still on treatment after more than 9 months. PET scan responses predicted subsequent computed tomography responses. Interpretation Imatinib at a dose of 400 mg twice daily is well tolerated during the first 8 weeks, side-effects diminish with continuing treatment, and it has significant activity in patients with advanced GISTs. Our results provide evidence of a role for KIT in GISTs, and show the potential for the development of anticancer drugs based on specific molecular abnormalities present in cancers.

18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Stroobants S, Goeminne J, Seegers M, Dimitrijevic S, Dupont P, Nuyts J Martens M, van den Borne B, Cole P, Sciot R, Dumez H, Silberman S, Mortelmans L, van Oosterom A. Eur J Cancer 2003;39(14):2012-20. Abstract: Imatinib mesylate (Glivec(R), formerly ST1571) is the first effective systemic treatment for gastrointestinal stromal tumours (GISTs). Major changes in tumour volume, however, tend to occur late after the start of treatment. The aim of this study was to evaluate if [F-18]-fluorodeoxyglucose-positron emission tomography (FDG-PET) can be used for the early evaluation of response to imatinib mesylate treatment in soft-tissue sarcomas (STS). 21 patients (17 GIST, 4 other STS) underwent FDG-PET imaging prior to and 8 days after the start of treatment. PET response (European Organization for Research and Treatment (EORTC) guidelines) was observed in 13 GISTs (11 Complete Responders, 2 partial responders. Subsequent computerised tomography (CT) response Response Evaluation Criteria in Solid Tumours (RECIST) was observed in 10 of these patients after a median follow up of 8 weeks. Stable or progressive disease was observed on PET in 8 patients and none of them achieved a response on CT. PET response was also associated with a longer progressionfree survival (PFS) (92% versus 12% at I year, P = 0.00107). We conclude that FDG-PET is an early and sensitive method to evaluate an early response to imatinib treatment. (C) 2003 Elsevier Ltd. All rights reserved.

Lymph node staging in non-small-cell lung cancer with FDG-PET scan: A prospective study on 690 lymph node stations from 68 patients. Vansteenkiste JF, Stroobants SG, De Leyn PR, Dupont PJ, Bogaert J, Maes A, Deneffe GJ, Nackaerts KL, Verschakelen LA, Lerut TE, Mortelmans LA, Demedts MG. J ClinOncol 1998;16(6):2142-2149. Abstract: Purpose: To compare the accuracy of computed tomography-(CT) scan and the radiolabeled glucose analog F-18-fluoro-2-deoxy-D-glvcose (FDG) positron emission tomography (PET) visually correlated with CT (PET + CT) in the locoregional lymph node (LN) staging of non-small-cell lung cancer (NSCLC). Patients and Methods: Sixty-eight patients with potentially operable NSCLC underwent thoracic CT, PET, and invasive surgical staging (155), Imaging studies were read prospectively and blinded to the surgical and pathologic data. A five-point visual scale was used for the interpretation of LNs on PET. Afterwards, with knowledge of the pathology, the relationship between standardized uptake values (SUVs)and the presence of metastasis in LNs was explored in a receiver operating characteristic (ROC) analysis, and the likelihood ratios (LRs) for SUVs of LNs were determined. Results : ISS was available for 690 LN stations. CT correctly identified the nodal stage in 40 of 68 patients (59%), with understaging in 12 patients and overstaging in 16 patients. PET + CT was accurate in 59 patients (87%), with understaging in five patients and overstaging in four patients. In the detection of locally advanced disease (N2/N3), the sensitivity, specificity, and accuracy of CT were 75%, 63%, and 68%, respectively. for PET + CT, this was 93%, 95%, and 94% (P = .0004). In the ROC curve, the best SUV threshold to distinguish benign from malignant LNs was 4.40. The analysis with this SUV threshold was not superior to the use of a five-point visual scale. The LR of a SUV less than 3.5 in an LN was 0.152; for a SUV between 3.5 and 4.5, it was 3.157; and for a SUV greater than 4.5, it was 253.096. Conclusion: PET + CT is significantly more accurate than CT alone in LN staging of NSCLC, A fivepoint visual scale is as accurate as the use of an SUV threshold for LNs in the distinction between benign and malignant nodes. The very high negative predictive value of mediastinal PET could reduce the need for mediastinal ISS in NSCLC substantially.

[F-18]FDG PET monitoring of tumour response to chemotherapy: does [F-18]FDG uptake correlate with the viable tumour cell fraction? Spaepen K, Stroobants S, Dupont P, Bormans G, Balzarini J, Verhoef G, Mortelmans L, Vandenberghe P, De Wolf-Peeters C. Eur J Nucl Med Mol Imaging 2003;30(5):682- 688. Abstract: Because metabolic changes induced by chemotherapy precede the morphological changes, fluorine-18 fluorodeoxyglucose positron emission tomography ([F-18]FDG PET) is thought to predict response to therapy earlier and more accurately than other modalities. To be a reliable predictor of response, changes in tumour [F-18]FDG uptake should reflect changes in viable cell fraction, but little is known about the contribution of apoptotic and necrotic cancer cells and inflammatory tissue to the [F-18]FDG signal. In a tumour mouse model we investigated the relation between chemotherapy-induced changes in various tumoral components and tumour uptake and size. SCID mice were subcutaneously inoculated in the right thigh with 5x10(6) Daudi cells. When the tumour measured 15-20 mm, Endoxan was given intravenously. At different time points [1-15 days (d1- d15) after the injection of Endoxan], ex vivo autoradiography and histopathology were performed in two mice and [F-18]FDG uptake in the turnout and tumour size were correlated with the different cell fractions measured with flow cytometry in five mice. At d1/d3, similar reductions in [F-18]FDG uptake and viable tumoral cell fraction were observed and these reductions preceded changes in tumour size. By d8/d10, [F-18]FDG uptake had stabilised despite a further reduction in viable tumoral cell fraction. At these time points a major inflammatory response was observed. At d15, an increase in viable turnout cells was again observed and this was accurately predicted by an increase in [F-18]FDG uptake, while the tumour volume remained unchanged. In contrast with variations in tumour volume, [F-18]FDG is a good marker for chemotherapy response monitoring. However, optimal timing seems crucial since a transient increase in stromal reaction may result in overestimation of the fraction of viable cells.

Prognostic value of pretransplantation positron emission tomography using fluorine 18-fluorodeoxyglucose in patients with aggressive lymphoma treated with high-dose chemotherapy and stem cell transplantation. Spaepen K, Stroobants S, Dupont P, Vandenberghe P, Maertens J, Bormans G, Thomas J, Balzarini J, De Wolf- Peeters C, Mortelmans L, Verhoef G. Blood 2003;1:102(1):53-9. Abstract: The study assessed the prognostic value of fluorine 18-fluorodeoxyglucose positron emission tomography([18F]FDG-PET) after salvage chemotherapy before high-dose chemotherapy with stem cell transplantation (HDT/SCT) in patients with induction failure or relapsing chemosensitive lymphoma. Retrospective analysis of the clinical and conventional imaging data of 60 patients scheduled for HDT/ SCT was performed in parallel with the analysis of the [18F]FDG-PET results. To determine the ability of [18F]FDG-PET to predict clinical outcome, PET images were reread without knowledge of conventional imaging and clinical history. Presence or absence of abnormal [18F]FDG uptake was related to progression- free survival (PFS) and overall survival (OS) using Kaplan-Meier survival analysis. Thirty patients showed a negative [18F]FDG-PET scan before HDT/SCT; 25 of those remained in complete remission, with a median follow-up of 1510 days. Two patients died due to a treatment-related mortality but without evidence of recurrent disease at that time (228-462 days). Only 3 patients had a relapse (median PFS, 1083 days) after a negative [18F]FDG-PET scan. Persistent abnormal [18F]FDG uptake was seen in 30 patients and 26 progressed (median PFS, 402 days); of these 26, 16 died from progressive disease (median OS, 408 days). Four patients are still in complete remission after a positive scan. Comparison between groups indicated a statistically significant association between [18F]FDG-PET findings and PFS (P <.000001) and OS (P <.00002). [18F]FDG-PET has an important prognostic role in the pretransplantation evaluation of patients with lymphoma and enlarges the concept of chemosensitivity used to select patients for HDT/SCT.

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