18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec®)
Introduction
Traditionally, the response to cancer treatment in solid tumours is evaluated by subsequent clinical or radiological assessments of target lesions and is defined as a significant decrease in measurable tumour dimensions 1, 2. There are, however, important limitations to the evaluation of tumour response by volume changes, especially in soft-tissue sarcomas (STS). Accurate measurement of tumour dimensions can be extremely difficult in non-well defined lesions like bone, bowel or peritoneal metastases. Reduction in the viable tumour cell fraction does not always result in a volume reduction since tumour tissue can be replaced by necrotic or fibrotic tissue and morphological images are unable to differentiate between these different tissue types. Furthermore, volume changes are rather late events. Usually, the first evaluation of objective responses measured by computerised tomography (CT) are performed not earlier than 2–3 months after the start of treatment because earlier changes are seldom significant. Therefore, patients are often unnecessarily exposed to ineffective, poorly tolerated, toxic or expensive treatments during a prolonged time. Finally, the new antivascular and cytostatic agents aim at tumour growth stabilisation rather than tumour shrinkage and thus no major volume changes are to be expected. To evaluate treatment efficacy, other criteria for response assessment need to be defined.
In recent years, metabolic imaging with positron emission tomography (PET) has become increasingly important in cancer management. The most frequently used radiotracer is [18F]-fluorodeoxyglucose, (FDG), a glucose analogue that is preferentially ‘trapped’ in fast-metabolising cells, such as those in malignant tumours [3]. Initially, FDG-PET was used in the diagnosis and staging of malignancies 4, 5, but, more recently, promising results have also been obtained in the evaluation of the response to treatment 6, 7, 8, 9, 10, 11, 12. Because glucose provides the primary source of carbons for the de novo synthesis of nucleic acids, lipids and amino acids, FDG uptake, a marker of the glucose metabolism is closely related to the number of viable cells [13] and the proliferation capacity of these cells [14]. Treatment-induced changes resulting in tumour cell death or growth arrest should therefore result in a subsequent reduction in FDG uptake, making this technique a sensitive and early marker of response. A number of small clinical trials have indeed indicated that quantification of changes in FDG uptake may provide an early and sensitive pharmacodynamic marker of the cytotoxic or cytostatic effect of anticancer drugs and result in improved monitoring of tumour response to anticancer drugs at a clinical and sub-clinical level as previously described by the European Organization for Research and Treatment of Cancer (EORTC) PET study group [15].
In this study, we examined the value of FDG-PET in the assessment of early tumour response to therapy with imatinib mesylate (Glivec®, formerly STI571, Novartis Pharma AG, Basel, Switzerland) in patients with different STS. Imatinib mesylate is an oral, bio-available, small molecule, that is an inhibitor of certain receptor tyrosine kinases involved in cell signalling, including KIT [16]. Gastrointestinal stromal tumours (GISTs) are rare neoplasms that are thought to arise from the mesenchymal cells of the gastrointestinal tract. The majority of GISTs are characterised by mutations in the KIT gene, which can cause a ligand-independent activation of its tyrosine kinase function and play a critical role in tumorigenesis, by promoting tumour growth and preventing apoptosis 17, 18. Inhibition of this KIT-driven growth pathway by imatinib mesylate has shown very promising clinical results in the treatment of patients with advanced GISTs, which are highly refractory to chemotherapy 19, 20, 21. Although most patients experienced major and rapid symptom relief, objective tumour response as evaluated by anatomical imaging (CT or magnetic resonance imaging (MRI)) occurred often only after several months. Therefore, the aim of this study was to evaluate if metabolic imaging using FDG-PET can be used for the earlier and more sensitive evaluation of the response of STS to treatment with imatinib mesylate.
Section snippets
Patients
All patients from the University Hospital Gasthuisberg, included in the phase I/II trial of the EORTC-STBSG (Soft Tissue and Bone Sarcoma Group study) investigating the maximum tolerated dose (MTD) (phase I) and efficacy (phase II) of imatinib mesylate in the treatment of advanced STS, were also prospectively evaluated using a PET protocol. The protocol had been approved by the EORTC New Treatment Committee, the EORTC Protocol Review Committee and the local Medical Ethics Committee. All
Patients
24 STS patients, enrolled in one of the two EORTC trials, were included in the PET sub-study. Histology was GISTs in 19 patients, fibrosarcomas in 2, synovial sarcomas in 2 and leiomyosarcoma in 1 patient. Baseline PET showed high FDG uptake in 17/19 GISTs and moderate to high uptake in 4/5 of the other sarcomas. 3 patients (two GISTs, one synovial sarcoma) were excluded for PET follow-up because the tumour was not FDG avid. Therefore, 21 patients were available for further analysis and their
Discussion
Metabolic imaging with FDG-PET seems to be an excellent tool to evaluate treatment efficacy in STS patients treated with imatinib. A complete metabolic response was achieved within 1 week in most of the responding patients (all GISTs) and preceded CT response by several weeks. Furthermore, early metabolic response was associated with a significant longer PFS (P=0.00107).
The better understanding of the pathophysiology of different cancer types has led to the development of a whole new class of
Acknowledgments
The authors want to thank colleagues from the radiopharmacy for their supply of FDG, the nurses and technologists from the PET for the patient studies and S. Vleugels for his technical support. We also want to thank the trial nurses for collecting the CT and outcome data, and Peter Vermaelen for the quantitative analysis of the PET data. This study was supported, in part, by a grant from Novartis Oncology, Novartis Pharma AG, Basel, Switzerland.
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