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The Oncologist, Vol. 13, No. suppl_2, 4-7, April 2008; doi:10.1634/theoncologist.13-S2-4
© 2008 AlphaMed Press

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Response Evaluation of Gastrointestinal Stromal Tumors

Haesun Choi

University of Texas, M. D. Anderson Cancer Center, Houston, Texas, USA

Key Words. Gastrointestinal stromal tumors • Response evaluation • Computed tomography

Correspondence: Haesun Choi, M.D., University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 57, Houston Texas 77030, USA. Telephone: 713-792-8177; Fax: 713-745-1302; e-mail: hchoi{at}di.mdacc.tmc.edu

Received August 20, 2007; accepted for publication November 9, 2007.

Disclosure: No potential conflicts of interest were reported by the author, planners, reviewers, or staff managers of this article.


   ABSTRACT
Top
 Abstract
Introduction
 Response Evaluation
 Surveillance
 Conclusions
 References
 
Clinical management of patients with gastrointestinal stromal tumors (GISTs) has dramatically changed with the introduction of novel therapeutics, such as imatinib mesylate. This has created a need to re-evaluate the existing criteria used to assess treatment response. The current Response Evaluation Criteria in Solid Tumors are based on unidimensional tumor size, and do not take into account changes in responding GISTs such as a decrease in tumor density and decrease in the number of intratumoral vessels with computed tomography (CT). Positron emission tomography (PET) has been found to be highly sensitive in detecting early response, and to be useful in predicting long-term response to imatinib in patients with metastatic GIST; however, widespread use of PET is limited because of a lack of scanner availability and cost constraints. Modified CT criteria using a combination of tumor density and tumor size are promising in early response evaluation, and have excellent prognostic value. Identifying appropriate treatment response criteria is essential to optimize treatment for patients with GIST.


   INTRODUCTION
Top
 Abstract
 Introduction
Response Evaluation
 Surveillance
 Conclusions
 References
 
Gastrointestinal stromal tumors (GISTs) are a subset of soft tissue sarcomas that develop primarily along the gastrointestinal tract and often spread within the abdomen. While GISTs account for only 0.2% of all gastrointestinal tumors, 80% of all gastrointestinal sarcomas are GISTs [1]. The prognosis for GIST has traditionally been notoriously poor [2, 3], with a dearth of effective therapies. However, clinical management of GIST patients has changed dramatically. With the identification of Kit receptor within the interstitial cells of Cajal of tumor cells and the introduction of a Kit receptor blocker, imatinib mesylate (Gleevec®, Novartis Pharmaceuticals Corporation, East Hanover, NJ), there has been a dramatic response in advanced disease. This dramatic response to imatinib has redefined not only the clinical management of GIST patients but also the response evaluation in imaging.

The current international Response Evaluation Criteria in Solid Tumors (RECIST) identify computed tomography (CT) and magnetic resonance imaging (MRI) as the best available and most reproducible methods for measuring target lesions [4]. In GIST, positron emission tomography (PET) using fluorine-18-fluorodeoxyglucose (18FDG) has been shown to be highly sensitive in detecting early response and to be useful to predict the long-term response to imatinib in patients with metastatic GISTs expressing c-Kit receptor tyrosine kinase [5]. Unfortunately, access to PET technology is still limited for GIST patients because of scanner availability and cost constraints. In some instances, glucose uptake before treatment is not sufficient for detection by 18FDG-PET. Our recent study showed that 36 of 173 (21%) lesions, ranging in size from 1.0 to 4.7 cm, did not demonstrate appreciable glucose uptake on pretreatment 18FDG-PET [6]. Among these 36 lesions, 17 (47%) were >2 cm in size (unpublished data). CT is widely accessible and is currently the imaging modality of choice in monitoring GIST patients treated with imatinib during the course of treatment and surveillance.


   RESPONSE EVALUATION
Top
 Abstract
 Introduction
 Response Evaluation
Surveillance
 Conclusions
 References
 
GISTs can occur anywhere along the gastrointestinal tract and rarely within the peritoneum. Contrast-enhanced CT is a powerful technique for GIST diagnosis, allowing for characterization of tumors [7] (Fig. 1). Once GIST is treated, the tumor size usually decreases upon response. In some responding tumors, the tumor size increases [6] as a result of intratumoral hemorrhage, necrosis, or myxoid degeneration. More dramatic changes in responding GISTs, how-ever, occur within the tumor mass; the density of the tumor decreases significantly, as does the number of intratumoral vessels. The tumor becomes homogeneous and hypodense (Figs. 1 and 2). The enhancing components within the tumor disappear. In contrast, tumor density change can be seen within a month and as early as 1 week of imatinib treatment. In many tumors, the decrease in tumor size is only minimal at an early post-treatment stage (Fig. 1), failing to satisfy the traditional response criteria, RECIST.


Figure 1
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  		Figure 1. Typical appearance of a responding gastrointestinal stromal tumor (GIST) in a man aged 70 years with a metastatic gastric GIST. (A): An enhanced computed tomography image obtained prior to imatinib treatment shows large hepatic and peritoneal metastases. Note the tumor vessels within the enhancing solid component along the periphery. (B): The tumor has become homogeneous and hypodense at 2 months of treatment. Notice that the tumor vessels and peripheral tumor nodules are no longer evident, with little, if any, decrease in tumor size.

 


Figure 2
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  		Figure 2. Typical appearance of a responding gastrointestinal stromal tumor (GIST) in a man aged 56 years with a metastatic gastric GIST to the liver. (A): A contrast-enhanced computed tomography (CT) image obtained prior to imatinib treatment shows an enhancing hepatic metastasis in segment 3 of the left lobe of the liver. Follow-up CT scans obtained at 2 months (B) and 4 months (C) show a continuous decrease in tumor size from 3.3 cm prior to treatment to 2.3 cm and 1.9 cm, respectively. Notice the dramatic changes in tumor density from 63 HU prior to treatment to 38 HU at 2 months and 32 HU at 4 months. The tumor becomes hypodense and homogeneous quickly.

 
Based on these clinical observations, 173 lesions of advanced GIST were analyzed on CT images for their subjective and objective responses to imatinib treatment. The subjective evaluation was performed based on the changes in overall tumor status (OTS), a combination of tumor size, density, and vascularization. The objective evaluation was performed based on the measurements of tumor density (HU) and size (cm). These CT responses were compared with PET responses (maximum standardized uptake value [SUVmax]) on 18FDG-PET evaluated based on the European Organization for Research and Treatment of Cancer 1999 criteria [6]. That study showed that tumor size and mean HU on CT and SUVmax on PET all decreased significantly at 8 weeks (p = .0025) (Fig. 3) [6]. There was a high correlation between the responses based on OTS on CT and SUVmax on 18FDG-PET (Table 1) and a trend toward a good correlation between HU density and SUVmax [6]. The tumor size change by the RECIST, however, showed no correlation with PET response (Table 2) [6]. In an attempt to identify better response evaluation criteria than "tumor size" on CT, " good response" on 18FDG-PET was redefined as a decrease in SUV <70% from baseline or a drop in the absolute value of SUVmax <2.5, based on the work of Van den Abbeele et al. [5]. From these data, 97% of good responders on 18FDG-PET had a ≥10% decrease in tumor size or a ≥15% decrease in tumor density on CT at 8 weeks of imatinib treatment (Table 3) [8]. These modified CT criteria have been shown to be highly capable of separating responders and nonresponders and provide an excellent prognostic indicator in terms of progression-free survival (Fig. 4) [9], although further validation is needed in larger populations.


Figure 3
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  		Figure 3. Objective tumor response evaluation on computed tomography (CT) and fluorine-18-fluorodeoxyglucose positron emission tomography (18FDG-PET). (A): Change in mean tumor size (cm) on CT. The decrease in mean tumor size at 2 months after treatment was significant (p = .0025, t-test; p = .0013, signed-rank test). (B): Change in tumor density (HU) on CT. The decrease in mean HU at 2 months after treatment was significant (p < .0025, t-test; p < .0011, signed-rank test). (C): Change in mean glucose metabolism, maximum standardized uptake value (SUVmax), on 18FDG-PET images. The decrease in mean SUVmax at 2 months after treatment was significant (p < .0001, t-test; p < .0001, signed-rank test).

 


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  		Table 1. Association between OTS on CT and SUVmax by grade of change after treatment

 


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  		Table 2. Association between tumor size and SUVmax by grade of change after treatment

 


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  		Table 3. Relationship between change in tumor size and tumor density on CT and tumor response by 18FDG-PET (n = 40)

 


Figure 4
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  		Figure 4. Progression-free survival in good and poor responders by fluorine-18-fluorodeoxyglucose positron emission tomography (18FDG-PET) and new computed tomography (CT) response criteria. (A): The new CT response evaluation criteria based on a combination of tumor size and density were able to separate responders and nonresponders clearly in terms of long-term progression-free survival up to 27 months (p = .04), as did the 18FDG-PET response criteria (p = .01) (B). From Choi H, Charnsangavej C, Faria S et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: Proposal of new computed tomography response criteria. J Clin Oncol 2007;25:1753–1759. Reprinted with permission from the American Society of Clinical Oncology.

 

   SURVEILLANCE
Top
 Abstract
 Introduction
 Response Evaluation
 Surveillance
Conclusions
 References
 
Once GIST patients are treated, the main role of imaging is surveillance and early detection of recurrence or disease progression. Traditionally, diagnosis of recurrence or progression on imaging is based on an increase in tumor size and identification of new lesions at either local or distant sites. In GISTs, an "increase in tumor size" is still important as long as the overall appearance of the tumor is thoroughly scrutinized for changes in tumor density and degree and pattern of enhancement on contrast-enhanced CT images. In addition, it should be noted that recurrence in GIST can occur within the treated hypodense tumor without changing the tumor size (Fig. 5) [7]. Development of an intratumoral nodule is often the first sign of progression and should be added to conventional progression criteria in monitoring GIST patients.


Figure 5
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  		Figure 5. Recurrence with a new intratumoral nodule in a woman aged 59 years with recurrent gastric gastrointestinal stromal tumor in the omentum. (A): Contrast-enhanced pre-treatment computed tomography (CT) scan shows a large heterogeneous omental mass (arrow) with a slight enhancement abutting the anterior surface of the stomach. (B): A 7-month follow-up CT image shows that the treated mass (arrow) has become homogeneous, with a decrease in density and size. (C): A contrast-enhanced CT scan obtained 11 months after treatment shows two new, small nodules (arrows) within the treated mass. These nodules were surgically confirmed to be viable tumor. From Hong X, Choi H, Loyer EM et al. Gastrointestinal stromal tumor: Role of CT in diagnosis and in response evaluation and surveillance after treatment with imatinib. Radiographics 2006;26:481–495. Reprinted with permission from the Radiological Society of North America.

 
With recognition of the new features of GISTs, CT remains an excellent imaging modality of choice to monitor disease during the course of treatment and surveillance. It should be noted, however, that 18FDG-PET should be used whenever the CT findings are inconclusive or inconsistent with the clinical findings.


   CONCLUSIONS
Top
 Abstract
 Introduction
 Response Evaluation
 Surveillance
 Conclusions
References
 
Size-based response criteria such as the RECIST significantly underestimate the response to imatinib in GIST. Subjective evaluation using changes in tumor nodules, density, and tumor vascularization, in addition to changes in tumor size, is the best way to evaluate response by CT. Objective criteria using a combination of tumor density (>15% change) and modified tumor size (>10%) are promising in early response evaluation and have excellent prognostic value. Identifying an intratumoral nodule within the treated GIST is a unique and important imaging finding in recurrent GIST.


   REFERENCES
Top
 Abstract
 Introduction
 Response Evaluation
 Surveillance
 Conclusions
 References
 

  1. Miettinen M, Lasota J. Gastrointestinal stromal tumors (GISTs): Definition, occurrence, pathology, differential diagnosis and molecular genetics. Pol J Pathol 2003;54:3–24.[Medline]
  2. Nishida T, Hirota S. Biological and clinical review of stromal tumors in the gastrointestinal tract. Histol Histopathol 2000;15:1293–1301.[Medline]
  3. Strickland L, Letson GD, Muro-Cacho CA. Gastrointestinal stromal tumors. Cancer Control 2001;8:252–261.[Medline]
  4. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–216.[Abstract/Free Full Text]
  5. Van den Abbeele AD, Badawi RD, Cliché J-P et al. 18F-FDG-PET predicts response to imatinib mesylate (Gleevec) in patients with advanced gastro-intestinal stromal tumors (GIST). Presented at the 38th Annual Meeting of the American Society of Clinical Oncology; May 18–21, 2002; Orlando, FL.
  6. Choi H, Charnsangavej C, Faria S et al. CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate treatment: A quantitative analysis correlated with FDG PET findings. AJR Am J Roentgenol 2004;183:1619–1628.[Abstract/Free Full Text]
  7. Hong X, Choi H, Loyer EM et al. Gastrointestinal stromal tumor: Role of CT in diagnosis and in response evaluation and surveillance after treatment with imatinib. Radiographics 2006;26:481–495.[Abstract/Free Full Text]
  8. Choi H, Charnsangavej C, Faria S et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: Proposal of new computed tomography response criteria. J Clin Oncol 2007;25:1753–1759.[Abstract/Free Full Text]
  9. Benjamin RS, Choi H, Macapinlac HA et al. We should desist using RECIST, at least in GIST. J Clin Oncol 2007;25:1760–1764.[Abstract/Free Full Text]



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