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Journal of Clinical Oncology, Vol 25, No 13 (May 1), 2007: pp. 1753-1759 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.3049 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
From the Division of Diagnostic Imaging and Department of Sarcoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Radiology, University of San Diego, San Diego, CA; and Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT Address reprint requests to Haesun Choi, MD, Division of Diagnostic Imaging, Box 368, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: hchoi{at}mdanderson.org
Purpose Response Evaluation Criteria in Solid Tumors (RECIST) are insensitive in evaluating gastrointestinal stromal tumors (GISTs) treated with imatinib. This study evaluates whether computed tomography (CT) findings of GIST after imatinib treatment correlate with tumor responses by [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) and develops reliable, quantitative, CT response criteria. Patients and Methods A total of 172 lesions selected by RECIST were evaluated in 40 patients with metastatic GISTs treated with imatinib. All patients had pretreatment and 2-month follow-up CTs and FDG-PETs. Multivariate analysis was performed using tumor size and density (Hounsfield unit [HU]) on CT and maximum standardized uptake value (SUVmax) on FDG-PET. Patients were observed up to 28 months. Results Mean baseline tumor size and density on CT were 5.3 cm and 72.8 HU, respectively, and mean baseline SUVmax on FDG-PET was 5.8. Thirty-three patients had good response on FDG-PET. A decrease in tumor size of more than 10% or a decrease in tumor density of more than 15% on CT had a sensitivity of 97% and a specificity of 100% in identifying PET responders versus 52% and 100% by RECIST. Good responders on CT at 2 months had significantly longer time to progression than those who did not respond (P = .01). Conclusion Small changes in tumor size or density on CT are sensitive and specific methods of assessing the response of GISTs. If the prognostic value of our proposed CT response criteria can be confirmed prospectively, the criteria should be employed in future studies of patients with GIST.
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the GI tract and is distinguished from true smooth muscle or neural tumors in approximately 95% of patients by expression of the KIT receptor tyrosine kinase (CD117). GISTs are now known to originate from the precursors of the interstitial cells of Cajal in the myenteric plexus. Most GISTs occur in the stomach (50%) and the small bowel (25%), but may occur anywhere in the GI tract as well as within the peritoneum. GISTs are known to have high malignant potential and none can be labeled definitely as benign.1 The therapeutic options for advanced GISTs have been limited until the remarkable efficacy of imatinib (Gleevec; Novartis, Basel, Switzerland), a tyrosine kinase inhibitor, was reported.2 Imatinib, a phenylaminopyrimidine derivative, is a small molecule that is known to inhibit the specific kinase action of ABL, the chimeric BCR-ABL fusion protein found in certain leukemias (such as chronic myelogenous leukemia), the platelet-derived growth factor receptors alpha and beta, and KIT, the product of the c-kit proto-oncogene.3-5 Since the introduction of this molecularly targeted drug, there has been increasing concern about the use of the traditional tumor response criteria.6-9 Our recent study indicated that the current international tumor response criteria, Response Evaluation Criteria in Solid Tumors (RECIST),10 using anatomic information only (tumor size), significantly underestimated the initial tumor response to imatinib in patients with metastatic GISTs.11 At the same time, dramatic changes were noted in tumor density, enhancing intratumoral tumor nodules, and tumor vessels on contrast-enhanced computed tomography (CT) images after imatinib treatment. Among these parameters, tumor density, as determined by measuring CT attenuation coefficient (Hounsfield unit [HU]), together with minor changes in tumor size that were insufficient for response by RECIST, provided the consistent quantitative means to evaluate the tumor response.8,9 Positron emission tomography (PET) using [18F]fluorodeoxyglucose (FDG) has been suggested as an early, sensitive marker of tumor response to anticancer drugs by monitoring the changes in glucose metabolism in tumors.12,13 Recently, FDG-PET has shown to be highly sensitive in detecting early response6,7,14 and to be useful to predict the long-term response of GIST to imatinib mesylate in patients with metastatic CD117-positive GIST.7,10,14 Unfortunately, access to PET is still limited for patients with GISTs, and in some lesions, the glucose uptake before treatment is not sufficient to be detected by FDG-PET. Our recent study showed that 36 (21%) of 173 lesions, ranging from 1.0 to 4.7 cm, did not demonstrate appreciable glucose uptake on pretreatment FDG-PET.11 Furthermore, the currently available European Organization for Research and Treatment of Cancer 1999 tumor response criteria12 that defined partial response by PET as a 25% decrease in maximum standardized uptake (SUVmax) may not be suitable for evaluating patients with GIST treated with imatinib mesylate. A recent study has demonstrated that, in good responders to imatinib, the absolute value of SUVmax decreased to below 2.5.14 This is similar to our recent observations. We have also observed a mean decrease of greater than 90% with a minimum of 65% in SUVmax in good responders (unpublished data). The purposes of the study were to determine whether the changes on CT in advanced GIST after treatment with imatinib correlated with the changes in glucose metabolism on FDG-PET when a more than 70% decrease in SUVmax to an absolute value of less than 2.5 was used to define a good response, and to determine if CT criteria could be used in quantitative response evaluation and possibly as prognostic indicators.
Patients A total of 109 patients with metastatic GIST treated with a daily dose of 400 to 800 mg of imatinib at The University of Texas M.D. Anderson Cancer Center during the period of December 2000 to September 2001 were selected for this analysis. Among these, 106 patients were enrolled onto the Intergroup phase III study and three were treated on the basis of compassionate use of an investigational new drug (use of an investigational new drug outside of an ongoing clinical trial under US Food and Drug Administration and institutional approval). The studies were conducted under the approval of the institutional review board, and all of the patients who participated signed informed consent forms. Forty-four patients of 109 had both CT and FDG-PET at our institution within 1 week of each other before treatment and at 2 months after treatment. Among these, four patients were excluded due to lack of measurable lesions by RECIST definitions. A total of 172 lesions in 40 patients were selected on the basis of RECIST10 for this study: 107 in the liver, 59 in the peritoneal cavity, two in the abdominal wall, and four in the pleura. Lesions smaller than 1.5 cm were excluded. There were 19 males and 21 females, with an age range of 28 to 86 years. All 40 patients were observed with CT up to 28 months after treatment.
Imaging Techniques FDG-PET was performed using a CTI HR+ PET scanner (Siemens Inc, Knoxville, TN) after administration of 10 to 15 mCi of [18F]FDG. All patients had nothing by mouth at least 6 hours before being scanned. After a 60-minute uptake phase, patients were scanned from the neck to the pelvis, according to the following parameters: 5-minute emission scan and 3-minute transmission scan (for attenuation correction) per field of view in a two-dimensional mode. The images were interpreted using volumetric projection and multiple orthogonal projection analysis.
Data Analysis Tumor size. Tumor size was measured in the longest cross-sectional dimension for each lesion at each time point using an Advanced workstation (GE Medical Systems). Based on RECIST, the sum of the longest dimensions of selected lesions in each patient was computed, and the absolute and percent changes of the sum from the pretreatment evaluation to the 2-month evaluation were computed for each patient. The changes in tumor size of each patient were then correlated with the changes in SUVmax on FDG-PET. CT attenuation coefficients. On an Advanced Workstation (GE Medical Systems), we measured the CT attenuation coefficient (density) of each tumor in HU by drawing a region of interest around the margin of the entire tumor. In the cases in which the patients were scanned with triphasic techniques, the portal venous phase was used for the tumor density measurement. The tumor density measurements of all lesions were combined and a mean HU for each patient was computed. Then, the absolute and percent changes in CT density from the pretreatment evaluation to the 2-month evaluation were computed for each patient. The changes in HU of each patient were then correlated with the changes in SUVmax on FDG-PET. The reliability of different monitors (CT operator's consoles, Advanced Workstation, and Stentor workstations [Stentor Inc, Brisbane, CA] in a radiologist's office) was tested before measuring the CT attenuation coefficient of tumors on CT. On the basis of our initial analysis,11 the absolute values of HU of each lesion were chosen for tumor density measurement. SUV on FDG-PET. Using vendor-specific software for Siemens/CTI HR+ PET scanner, SUVmax was measured by drawing a region of interest slightly outside each lesion corresponding to those used for HU measurement on the CT image and adjusted for body weight. The SUVmax values of all tumors were combined, and a mean SUVmax was computed for each patient. Then, the absolute and percent changes from the pretreatment evaluation to the 2-month evaluation were computed for each patient. The values of SUVmax that were decreased by at least 70%, to less than 2.5 at 2 months after treatment, were graded as good responses (GoodR). All other responses, including stable or any increase in SUVmax, were considered poor responses (PoorR). TTP. Tumor progression was identified on the basis of the following CT findings: appearance of new lesions or metastasis, appearance of new intratumoral tumor nodules or increase in the size of existing intratumoral tumor nodules, or increase in overall tumor size by more than 20% in the absence of post-treatment hypodense change.
Statistical Analysis
In 40 patients, the average SUVmax on FDG-PET in each patient ranged from 1.4 to 19.7 (mean, 5.8) before treatment and from 0 to 13.7 (mean, 1.4) at 2 months after treatment. Tumor size ranged from 2.0 to 16.5 cm (mean, 5.3 cm) before treatment and from 1.4 to 13.1 cm (mean, 4.2 cm) at 2 months post-treatment on CT. Tumor density ranged from 45.4 to 156.8 HU (mean, 72.8 HU) before treatment and from 10.0 to 135.0 HU (mean, 53.8 HU) at 2 months after treatment (Table 1).
Thirty-three (83%) of 40 patients showed GoodR on FDG-PET (Table 2). In good responders, tumor size decreased by a mean of 26% at 2 months after treatment, and 31 patients (94%) demonstrated a more than 10% decrease in tumor size. No patient with PoorR showed a more than 10% decrease in tumor size (Table 2). In good responders, tumor density (HU) decreased by a mean of 31% at 8 weeks after treatment, and 27 patients (82%) demonstrated a more than 15% decrease in HU. No patient with PoorR showed a more than 15% decrease in HU (Table 2). Ninety-seven percent of good responders showed either a 10% decrease in tumor size or a 15% decrease in tumor density on CT, but none in the PoorR group showed either 10% decrease in tumor size or 15% decrease in tumor density (Table 2). On the basis of these results, the new CT criteria for good response on CT were defined as follows: a more than 10% mean percent decrease in tumor size or a more than 15% mean percent decrease in tumor density (Table 3).
When RECIST were used in tumor response evaluation (best response, regardless of the time when it was defined), no significant difference was observed in long-term prognosis (TTP) between the good and poor responders (P = .35) for up to 28 months in both groups (Fig 1). When PET criteria or CT criteria of either a more than 10% decrease in maximum diameter or a more than 15% decrease in tumor density at 2 months after treatment were used, significant differences were observed in TTP between good and poor responders (P = .01 and P = .04, respectively) for up to 28 months (Figs 2 and 3). When the new CT criteria were used, 32 of 40 (80%) patients responded to imatinib, whereas when RECIST were used, 17 of 40 patients (43%) responded to imatinib (Table 4).
The treatment response of solid tumors traditionally has been evaluated on the basis of morphologic features (tumor size). RECIST partial response, a more than 30% decrease in the sum of the maximum diameters of all measurable lesions, is the current standard in assessing the response of solid tumors to anticancer therapy.10 These criteria were modified from older criteria that used a more than 50% decrease in the sum of the products of perpendicular diameters of all measurable lesions.15,16 Historical perspective of use of a more than 50% decrease in the products of perpendicular diameters as a partial response criterion goes back to the 1970s. A more than 50% decrease was accepted as a partial response criterion on the basis of an experiment of tumor measurement conducted by 16 clinicians, using solid spheres covered by foam rubber pads.17 Now that we can measure the size of lesions to a precision of tenths of millimeters with a computer on the cross-sectional images, such as CT or magnetic resonance imaging, the accuracy of current response criteria should be re-examined. The current response evaluation criteria by FDG-PET adopted by the European Organization for Research and Treatment of Cancer were developed on the basis of multiple previous small studies of various tumors.12 GIST was not included. The definition of partial response as a 25% decrease in SUVmax is based on the reproducibility of the SUVmax measurement,12 similar to the 50% size decrease on physical examination,17 rather than any correlation with clinically relevant end points such as TTP. Recently, Van den Abbeele et al14 reported that patients with an early decrease in an absolute value of SUVmax to less than 2.5 at 21 to 40 days after treatment with imatinib demonstrated a significantly better long-term progression-free survival relative to others. Jager et al18 reported that a decrease in SUVmax by 65% at 1 week after treatment indicated good responders. In our review, all responders demonstrated greater than 75% decrease in SUVmax at 2 months after treatment with imatinib mesylate, except for one who showed a 64% decrease. For this study, we used PET criteria of a more than 70% decrease in SUVmax relative to the pretreatment value, to an absolute value of SUVmax to less than 2.5, to be a good responder. This study confirmed our previous observation9 that RECIST significantly underestimated tumor response. Our data suggest that a more than 10% decrease in one dimension on CT at 2 months after treatment is adequate to identify good responders on FDG-PET and predicts a longer TTP. Furthermore, contrast-enhanced CT can demonstrate tumor characteristics, such as tumor density, enhancing tumor nodules, and tumor vessels, in addition to tumor size (Fig 4; Appendix Fig A1, online only). It is clear that the outside dimensions of a tumor mass may not accurately reflect how active the tumor is. Some lesions, despite clinical and PET response, actually increased in size (Fig 5). Decreased density of the responding tumors on CT is correlated with the development of tumor necrosis or cystic or myxoid degeneration. Tumor density also provides an additional measure of response to therapy, can be quantified objectively, and can be measured readily on clinical images (Figs A1 and 5). Once the CT technique is designed to provide an optimal portal venous phase (the time for the maximum hepatic enhancement and the best visualization of most lesions) for a specific scanner, and if the same CT technique is used for pre- and post-treatment evaluations, density measurement should be reproducible on an accurately calibrated workstation. Of note, however, is that arterial phase (bi- or triphasic dynamic imaging technique), although not used for density measurement, is also needed to optimize the visualization of all lesions and to observe changes in tumor vascularity and the pattern of enhancement before and after treatment.11
A combination of the values of tumor size and tumor density on CT (a 10% decrease in tumor size or a more than 15% decrease in tumor density at 2 months of treatment) predicted the TTP as well as the SUVmax. In our patients with metastatic GISTs, response evaluated by the new CT criteria was a significantly better predictor of TTP than ultimate partial response by RECIST (Table 4; Fig 3). We have also observed the inadequacy of RECIST in identifying responding tumors in other solid tumors, such as renal cell carcinomas (C.C., H.C.) or other sarcomas (R.S.B.), sporadically. This inadequacy seems particularly evident in patients undergoing targeted therapies, such as antiangiogenic agents or tyrosine kinase inhibitor treatments.19-21 In an early thalidomide trial at our institution, responding tumors showed significant changes in tumor perfusion without enough change in size to be classified as partial reasponse by RECIST (unpublished data). Similarly, changes in CT density of responding tumors have been published previously. In an SU11248 trial by Motzer et al,21 the responding metastatic renal cell tumors in the liver showed dramatic decrease in enhancement with little change in size on post-treatment CT. Although our criteria were derived from treatment of GIST with imatinib, these criteria might apply to other tumor types and to cytotoxic as well as targeted therapy. In conclusion, CT was a sensitive and specific method to assess the response of metastatic GISTs to imatinib: a decrease in tumor size of more than 10% or a decrease in tumor density of more than 15% had a sensitivity of 97% and a specificity of 100% in detecting patients with GoodR evaluated by PET criteria. These CT criteria were excellent predictors of tumor progression, as were PET criteria. RECIST substantially underestimated, especially at the early stage of treatment, the effect of imatinib on metastatic GIST and was a poor predictor of clinical benefit. These data can serve as a training set for the prognostic value of response with regard to TTP to be confirmed in an independent group of patients. If confirmed for GIST, extrapolation of these data to other tumors and other treatment approaches requires additional study.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Haesun Choi, Novartis Pharma; Homer A. Macapinlac, Siemens, GE Healthcare, Radiology Corporation of America (RCOA); Donald A. Podoloff, Biogen IDEC Inc (IDEC), Siemens, GE Healthcare, Bexxar; Robert S. Benjamin, Novartis Stock: N/A Honoraria: Haesun Choi, Novartis Pharma; Homer A. Macapinlac, Siemens, GE Healthcare, RCOA; Shreyaskumar R. Patel, Novartis, Amgen; Donald A. Podoloff, Bexxar, IDEC, GE Healthcare; Robert S. Benjamin, Novartis Research Funds: Homer A. Macapinlac, GE Healthcare Testimony: N/A Other: Robert S. Benjamin, Novartis
Conception and design: Haesun Choi, Chuslip Charnsangavej, Robert S. Benjamin Financial support: Donald A. Podoloff, Robert S. Benjamin Administrative support: Donald A. Podoloff, Robert S. Benjamin Provision of study materials or patients: Michael A. Burgess, Shreyaskumar R. Patel, Lei L. Chen, Robert S.Benjamin Collection and assembly of data: Haesun Choi, Silvana C. Faria, Homer A. Macapinlac, Robert S.Benjamin Data analysis and interpretation: Haesun Choi, Chuslip Charnsangavej, Homer A. Macapinlac, Robert S. Benjamin Manuscript writing: Haesun Choi, Chuslip Charnsangavej, Robert S. Benjamin Final approval of manuscript: Haesun Choi, Chuslip Charnsangavej, Silvana C. Faria, Homer A. Macapinlac, Michael A. Burgess, Shreyaskumar R. Patel, Lei L. Chen, Donald A. Podoloff, Robert S. Benjamin
Supported by NCI Contracts No. U01-CA70172-01 and N01-CM-17003. Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL; presented in part at the 9th Annual Meeting of the Connective Tissue Oncology Society, November 11-13, 2004, Montreal, Quebec, Canada. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Rosai J: Gastrointestinal tract, in Rosai J, Ewing J (eds): Ackerman's Surgical Pathology. St Louis, MO, Mosby Year-Book, 1996, pp 645-6932 2. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al: Effect of the tyrosine kinase inhibitor STI-571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344:1052-1056, 2001 3. Pietras K, Ostman A, Sjoquist M, et al: Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res 61:2929-2934, 2001 4. Buchdunger E, Zimmermann J, Mett H, et al: Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res 56:100-104, 1996 5. Oetzel C, Jonuleit T, Gotz A, et al: The tyrosine kinase inhibitor CGP 57148 (STI-571) induces apoptosis in BCR-ABL-positive cells by down-regulating BCL-X. Clin Cancer Res 6:1958-1968, 2000 6. Stroobants S, Goeminne J, Seegers M, et al: 18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Gleevec). Eur J Cancer 39:2012-2120, 2003[CrossRef][Medline] 7. Antoch G, Kanja J, Bauer S, et al: Comparison of PET, CT, and dual-modality PET/CT imaging for monitoring of imatinib (STI-571) therapy in patients with gastrointestinal stromal tumors. J Nucl Med 45:357-365, 2004 8. Choi H, Macapinlac H, Burgess M, et al: Correlation of computerized tomography (CT) and positron emission tomography (PET) in patients with metastatic GIST treated at a single institution with imatinib mesylate. Proc Am Soc Clin Oncol 22:819, 2003 (abstr 3290) 9. Choi H, Faria S, Benjamin R, et al: Monitoring treatment effects of STI-571 on gastrointestinal stomal tumors (GIST) with CT and PET: A quantitative analysis. Presented at Radiological Society of North America Scientific Program, Chicago, IL, December 1-6, 2002 10. 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 92:205-216, 2000 11. Choi H, Charnsangavej C, Faria SC, 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 183:1619-1628, 2004 12. Young H, Baum R, Cremerius U, et al: Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: Review and 1999 EORTC recommendations—European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer 35:1773-1782, 1999[CrossRef][Medline] 13. Marsden P, Sutcliffe-Goulden J: Principles and technology of PET scanning. Nucl Med Commun 21:221-224, 2000[CrossRef][Medline] 14. Van den Abbeele A, Badawi R, Cliche J, et al: 18F-FDG-PET predicts response to imatinib mesylate (Gleevec) in patients with advanced gastrointestinal stromal tumors (GIST). Proc Am Soc Clin Oncol 21a:403a, 2002 (abstr 1610) 15. Karnofsky DA: Meaningful clinical classification of therapeutic responses to anticancer drugs. Clin Pharmacol Ther 2:709-712, 1961[Medline] 16. World Health Organization: World Health Organization Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, World Health Organization, 1979, p 48 17. Moertel CG, Hanley JA: The effect of measuring error on the results of therapeutic trials in advanced cancer. Cancer 38:388-394, 1976[CrossRef][Medline] 18. Jager PL, Gietema JA, van der Graaf WT: Imatinib mesylate for the treatment of gastrointestinal stromal tumours: Best monitored with FDG-PET. Nucl Med Commun 25:433-438, 2004[CrossRef][Medline] 19. Ratain MJ, Eisen T, Stadler WM, et al: Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 24:2505-2512, 2006 20. Faivre S, Delbaldo C, Vera K, et al: Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 24:25-35, 2006 21. Motzer RJ, Michaelson D, Redman BG, et al: Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24:16-24, 2006 Submitted May 8, 2006; accepted February 12, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
) along the periphery. Note the multiple prominent tumor vessels (arrowheads). (B) CT scan obtained 2 months after treatment shows that the lesions (
