The Lessons of GIST—PET and PET/CT: A New Paradigm for Imaging Annick D. Van den Abbeele Dana-Farber Cancer Institute, Boston, Massachusetts, USA Key Words. Positron emission tomography • Computed tomography • Fluorodeoxyglucose Gastrointestinal stromal tumor • Imatinib mesylate Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

Abstract Traditional anatomic tumor response criteria are based on uni- or bidimensional changes in tumor size, and do not take into account changes in tumor metabolism, tumor density, or decrease in the number of intratumoral vessels. These changes are, however, all indicative of response to imatinib therapy in patients with gastrointestinal stromal tumor (GIST). In these patients, metabolic responses seen on positron emission tomography (PET) using fluorine-18-fluorodeoxyglucose (18 FDG) have been shown to be closely related to clinical benefit. Furthermore, these metabolic changes precede by weeks or months significant decrease in tumor size on computed tomography (CT). Conversely, lack of metabolic response on FDG-PET indicates primary resistance to the drug and may help identify patients who

would benefit from another therapy, while re-emergence of metabolic activity within tumor sites following a period of therapeutic response indicates secondary resistance to the drug. Newly proposed CT criteria using either no growth in tumor size or a combination of tumor density and size criteria have shown a close correlation with the predictive value results of FDG-PET. Thus, the integration of FDG-PET and CT, as in the combined hybrid PET/CT scanners now available, will not only optimize the evaluation of patients with GIST treated with molecularly targeted drugs, but may ultimately help shorten clinical trials, and accelerate drug development in this disease and other cancers as well. The Oncologist 2008;13(suppl 2):8–13

Introduction

based on tumor size, as measured by computed tomography (CT), lag weeks and months behind the 18FDG-PET imaging results [5, 6]. 18FDG-PET response is characterized by a marked decrease in the glycolytic metabolism of GISTs in all patients who respond to imatinib. This response can be seen 1 month after initiating therapy, and as early as 24 hours after treatment begins [5]. Tumor response to therapy in sarcomas, including GISTs, is best monitored by using both PET and CT. This dual monitoring can now be performed in one setting on combined hybrid PET/CT scanners, which facilitate both anatomic and functional tumor evaluation. 18FDG-PET scanning is effective in staging and restaging GISTs, and for evaluating therapeutic response to a variety of treatments. This paper summarizes some of the lessons we have learned about the

Traditional anatomic tumor response criteria, such as the World Health Organization (WHO) criteria and the Response Evaluation Criteria in Solid Tumors (RECIST), are not as useful for sarcomas as they are for other tumor types. This is because sarcomas, including gastrointestinal stromal tumors (GISTs), may not change size in response to therapy [1–4]. Because sarcomas often show high metabolic activity related to intense glycolysis, positron emission tomography (PET) using fluorine-18-fluorodeoxyglucose (18FDG) can be used to evaluate these tumors and the response to therapy. In patients with GIST treated with imatinib mesylate, responses seen on 18FDG-PET are closely related to clinical benefit while conventional objective response criteria

Correspondence: Annick D. Van den Abbeele, M.D., Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. Telephone: 617632-2595; Fax: 617-582-8574; e-mail: [email protected] Received August 20, 2007; accepted for publication September 25, 2007. ©AlphaMed Press 1083-7159/2008/$30.00/0 doi: 10.1634/theoncologist.13-S2-8

The Oncologist 2008;13(suppl 2):8–13 www.TheOncologist.com

Van den Abbeele

use of 18FDG-PET (or 18FDG-PET/CT) in GIST and reports on data that have either been published or presented at various national and international meetings since 2001.

Relevance of Baseline Evaluation Because 18FDG-PET imaging is a functional imaging study that can evaluate tumor metabolism over time, a baseline scan should always be obtained prior to initiating treatment. Conducting a baseline evaluation allows one to establish a denominator against which future studies or quantitative measurements, such as the standardized uptake value (SUV) or maximum SUV (SUVmax), can be compared. This denominator is essential for characterizing the metabolic response when using the European Organization for Research and Treatment of Cancer (EORTC) criteria, which are based on the magnitude of the change in SUV relative to baseline [7].

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other hand, even when a patient benefits from treatment, it may take weeks, months, or even years for these tumors to shrink on CT (Fig. 2). Importantly, 18FDG-PET scans performed soon after treatment begins may identify patients with primary resistance to the drug who may not benefit from this therapy, and for whom alternative treatment should be considered.

Response Evaluation 18

FDG-PET may be used to detect both short-term and long-term tumor responses that may not be apparent with CT. As mentioned earlier, 18FDG-PET responses can be observed as early as 24 hours after a single dose of imatinib. A significant change in SUVmax to 25% decrease in SUVmax relative to baseline can be seen within 1 month of starting imatinib therapy in all GIST patients responding to the drug (Figs. 1 and 2). On the

Figure 1. FDG-PET scans of a patient with metastatic GIST prior to and 1 month after imatinib therapy. (A): Coronal fluorine-18-fluorodeoxyglucose positron emission tomography (18FDG-PET) scan in a patient with a gastrointestinal stromal tumor metastatic to the abdomen, mesentery, peritoneum, and liver shows intense glycolytic activity in all tumor sites at baseline prior to initiating imatinib. (B): A restaging 18FDG-PET scan 1 month after initiating imatinib therapy shows complete resolution of abnormal 18FDG uptake in all tumor sites and no evidence of metabolically active disease, consistent with response to therapy.

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Figure 2. FDG-PET and correlating CT scans of a patient prior to and 1 month after imatinib therapy. (A): Coronal fluorine-18-fluorodeoxyglucose positron emission tomography (18FDG-PET) and axial 18FDG-PET scan slice, with corresponding axial computed tomography (CT) slice through the upper abdomen, in a patient with metastatic GIST prior to initiating imatinib shows intense 18FDG uptake in a large left upper quadrant mass arising from the stomach, a liver metastasis, and a small mass in the left lower quadrant. (B): After 1 month of imatinib therapy, there is interval resolution of abnormal glycolytic activity in all disease sites, consistent with response to imatinib therapy despite the fact that the gastric and hepatic lesions are stable by Southwest Oncology Group criteria (i.e., show a