Clinical Cancer Research Vol. 11, 6171-6176, September 1, 2005
© 2005 American Association for Cancer Research
Imaging, Diagnosis, Prognosis |
Effect of Angiosonography to Monitor Response During Imatinib Treatment in Patients with Metastatic Gastrointestinal Stromal Tumors
Ugo De Giorgi1,
Camillo Aliberti3,
Giorgio Benea3,
Matteo Conti2 and
Maurizio Marangolo1
Authors' Affiliations: 1 Istituto Oncologico Romagnolo, Department of Oncology and 2 Laboratory of Clinical Pharmacology and Toxicology, Santa Maria delle Croci Hospital, Ravenna; and 3 Department of Imaging, Delta Hospital, Lagosanto, Ferrara, Italy
Requests for reprints: Ugo De Giorgi, Istituto Toscano Tumori-Department of Oncology, San Giuseppe Hospital, Via Paladini 40, I-50053 Empoli, Florence, Italy. Phone: 39-349-222-1235; Fax: 39-0571-702671; E-mail: ugo_degiorgi{at}yahoo.com.
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Abstract
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Purpose: Gastrointestinal stromal tumor (GIST) metastases are typically intra-abdominal and hypervascular. We assessed the effect of angiosonography with a second-generation contrast agent to monitor response during imatinib treatment in patients with metastatic KIT+ GIST.
Experimental Design: Ten consecutive patients with known advanced KIT+ GIST were investigated with angiosonography and computerized tomography (CT). We also monitored the serum levels of the major angiogenic growth factor, vascular endothelial growth factor.
Results: Angiosonography showed a reduction in tumor vascularization of liver metastases during imatinib treatment in all cases. We observed a reduction in tumor vascularization before a reduction in tumor size. The tumor perfusion appeared reduced in the central part of the liver metastases. With a median follow-up of 18 months (range 3-33), a reduction in tumor vascularization was initially observed in all patients, but progressive disease was documented in four patients following imatinib treatment. CT documented tumor response according to standardized criteria in six patients, stable disease in four, and progressive disease according to angiosonography. The reduction of tumor perfusion at angiosonography correlated with the pseudocystic appearance at CT. The "nodule(s) within a mass" pattern of recurrence occurred in two patients with no difference observed between angiosonography and CT. Early decreasing serum vascular endothelial growth factor levels were observed in the two cases with higher pretreatment levels.
Conclusions: Imatinib could induce antiangiogenic and/or antivascular effects in GIST, and this effect could be easily monitored with angiosonography. Angiosonography might be a useful complement for monitoring the therapeutic effect of imatinib in these patients.
The use of imatinib in gastrointestinal stromal tumors (GIST) represents the first effective development of a targeted therapy for a solid neoplasm. Imatinib produces objective responses in nearly 50% to 55% of patients (median time to response, 3-4 months; range 1-12), and stable disease in 30% to 35% as measured with computerized tomography (CT) or magnetic resonance by standardized criteria (Southwest Oncology Group criteria, and Response Evaluation Criteria in Solid Tumors; refs. 1–3). These results correlated closely with findings of response based on metabolic functional imaging with fluorine-18 fluorodeoxyglucose positron emission tomography (PET) in 80% to 90% of patients, before any measurable changes were seen on CT (3, 4).
GIST metastases are typically intra-abdominal and hypervascular (5). The accuracy of ultrasound in the detection of intra-abdominal metastases from GIST is lower than CT or magnetic resonance, but the introduction of contrast agents led to new possibilities for functional imaging studies. BR1 (Sonovue, Bracco, Milan, Italy) is a new blood pool ultrasound second-generation contrast agent, which consists of stabilized microbubbles of a totally innocuous sulfur hexafluoride gas, which is of low solubility. It is isotonic to human plasma and devoid of antigenic potential, as it does not contain any proteineous material (6). BR1 allows angiosonography through continuous real-time examination during different vascular phases of contrast enhancement using low transmission power, expressed as mechanical index. We evaluated the effect of angiosonography with BR1 to monitor response during imatinib treatment (400 mg oral administration, once daily) in patients with metastatic GIST.
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Patients and Methods
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Patients. Between May 2002 and February 2004, 10 consecutive patients (8 males and 2 females) with known advanced KIT+ GIST were investigated with angiosonography and CT. Median age was 66 years (range, 35-85). A pathologic review in other centers was done in all cases. No patient was previously treated with imatinib. Patient characteristics before imatinib treatment are listed in Table 1. In addition, nine more patients were studied with both techniques in the follow-up after complete resection of GIST.
Imatinib treatment. All patients were treated with imatinib at the starting dose of 400 mg/d. The imatinib dose was modified during the treatment in patients with severe toxicities. In these cases, the treatment was briefly interrupted until toxicity recovery and then was restarted with the imatinib dose of 300 mg/d. In patients with progressive disease, the imatinib dose was increased to 800 mg/d, if possible, according to the tolerance and compliance of patients. In cases with minimal progressive disease with unresectable disease, continuing imatinib treatment at 400 mg/d was considered. In patients with massive progressive disease, the imatinib treatment was stopped.
Imaging techniques. The ultrasound examinations were done by means of a Sequoia digital ultrasound scanner (Acuson, Mountain View, CA) equipped with a wideband C5-2 MHz convex probe. Before contrast agent injection, the scanning plane of the abdomen that included the nodule(s) was determined. After the baseline ultrasound examination, all patients underwent angiosonography using BR1. Nonlinear imaging was done starting with high mechanical index and then reducing to a continuous low acoustic power (mechanical index = 0.20) for each patient. Twelve milliliters of a 5 mg/mL solution of BR1 were administered as an i.v. bolus. The whole vascular phase was studied, consisting of the arterial phase (15-30 seconds after the injection), the portal phase (30-60 seconds), and the sinusoidal phase (60-240 seconds). A second injection of BR1 was needed in some cases.
Moreover, patients underwent multi-phase helical CT (Mx8000, Philips Medical Systems, Eindhoven, the Netherlands). Each patient received a bolus of 120 mL of low-osmolar iodinated contrast medium (Iomeron 400, Iomeprol, Bracco, Milan, Italy).
PET scan was not regularly done. However, PET was done in cases with changes in tumor features at angiosonography and/or CT as in the case of progressive disease. PET scans were carried out using a PET tomograph (Advance scanner, GE Medical System, Waukesha, WI). PET was carried out after i.v. injection of 370 MBq of fluorodeoxyglucose; images were recorded after 60 to 90 minutes.
Study protocol. In patients with advanced GIST treated with imatinib, CT was done at baseline, at 1, 2, 4, and 6 months, and then every 3 months. Angiosonography was done before treatment, at 6 months, and then every 6 months in the first five cases, but at the same time points of CT in the next five. Two radiologists evaluated the percentage of sonographic contrast uptake during different vascular phases at each tumor site and compared results obtained by angiosonography and CT. In a single case, the last one (Table 1, patient 10), we did a strict evaluation with angiosonography at 1, 2, 4, 6, and 8 weeks in order to define the first time point of reduction in tumor vascularization during imatinib treatment. The study protocol was approved by the Institutional Review Board and patients provided written consent. In nine additional patients, in the follow-up after GIST complete resection, CT and angiosonography were done at the same time points every 3 to 6 months.
Vascular endothelial growth factor. We monitored the serum levels of the major angiogenic growth factor, vascular endothelial growth factor (VEGF), in all patients at baseline, at 1, 2, and 4 weeks, and then every month until treatment failure. The serum levels of VEGF were determined by ELISA. The analyses were carried out according to the manufacturer's recommendations (Human VEGF, Pierce Endogen, Rockford, IL).
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Results
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Overall, five patients had 
10 liver metastases, four patients had <10 liver lesions. Liver metastases appeared hypervascularized before imatinib treatment. Instead, only five peritoneal metastases in four patients were detected and appeared less vascularized than liver lesions.
Angiosonography showed a reduction in tumor vascularization of the liver metastases in all cases (Fig. 1). The tumor perfusion appeared reduced in the central part of the liver metastases. With a median follow-up of 18 months (range 3-33), a reduction in tumor vascularization was initially observed in all patients with liver metastases and in the patient with a retroperitoneal mass only. In four patients, angiosonography documented progressive disease after 12, 21, 24, and 27 months of imatinib treatment.
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Fig. 1. Angiosonography with BR1 of the right lobe of the liver in a patient with liver metastasis from GIST before and after 2 months of imatinib treatment. A, unenhanced sonography with detection of one lesion with small central hypoechoic area and hypoechoic halo around metastasis (arrow); B, following BR1 administration, in the same scan of (A), liver metastasis appears isoechoic with respect to intensely bright normal parenchyma in the portal phase (arrow); C, unenhanced sonography after 2 months of imatinib treatment shows one lesion with the same characteristics as unenhanced sonography before treatment (A; arrow); D, following BR1 administration, in the same scan of (C) after 2 months of imatinib treatment, liver metastasis appears hypoechoic and completely surrounded by intensely bright normal parenchyma in the portal phase (arrow).
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CT showed an initial tumor response according to standardized criteria in six patients (median time to response, 4 months; range 1-9), whereas in the other four patients, stable disease was documented lasting 12, 21, 24, and 24+ months, respectively. In these four patients, achieving initial stable disease based on CT, the first angiosonography done at 6 months, documented a reduction in tumor vascularization of 80%, 60%, >90%, and 70%, respectively. The reduction of tumor perfusion of the liver metastases reported at angiosonography correlated with the pseudocystic appearance which can be seen on post-contrast CT following imatinib treatment (Fig. 2). In four cases, during imatinib treatment, CT showed progressive disease according to angiosonography. In two cases with progressive disease after 21 and 24 months of treatment, the imatinib dose was increased to 800 mg/d, but these two patients experienced further progressive disease after 3 and 9 months, respectively.
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Fig. 2. Angiosonography with BR1 and CT of the right lobe in a patient with liver metastases from GIST after 12 months of imatinib treatment showing correspondence between the reduction of tumor perfusion at angiosonography with pseudocystic appearance at CT. A, angiosonography reveals a dishomogeneous lesion (1), whereas lesions 2 and 3 appear hypoechoic during the late arterial phase with evident reduction in vascularization; B, CT shows a lesion with a mixed appearance (1), whereas lesions 2 and 3 show a pseudocystic appearance.
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Of the four patients with recurrent disease, two presented a "classical" progressive disease with both regrowth of preexisting lesions and new sites of disease was revealed at both angiosonography and CT with an increase of fluorodeoxyglucose uptake on PET scan. In two other cases, a new pattern of progressive disease with "nodule(s) within a mass" only was revealed at both angiosonography and CT, but PET scan appeared negative (Fig. 3) or with a very small positivity (Fig. 4), at first recurrence.
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Fig. 3. Metastatic GIST in a patient with initial positive response to imatinib treatment showing the "nodule(s) within a mass" pattern of progression during imatinib treatment (case 1). A, after 24 months of imatinib treatment, angiosonography reveals two small contrast-enhanced nodules (arrows) within a lesion hypoechoic during the late arterial phase with evident reduction in vascularization; B, CT obtained at the same time point of (A) shows two enhanced nodules (arrows) within the matrix of a low-attenuation mass; C, PET scan obtained at the same time point of (A) and (B) shows lack of fluorodeoxyglucose uptake in the treated lesion; D, after 33 months of imatinib treatment, despite the increase of the dose of imatinib to 800 mg/d, angiosonography reveals the increase of the size of the two contrast-enhanced nodules (arrows); E, CT obtained at the same time point of (D) shows the increase of the size of the two enhanced nodules (arrows); F, PET scan obtained at the same time point of (D) and (E) shows a focal area of increased fluorodeoxyglucose uptake in the treated lesion (arrow).
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Fig. 4. Metastatic GIST in a patient with initial positive response to imatinib treatment showing the "nodule(s) within a mass" pattern of progression during imatinib treatment (case 2). A, after 27 months of imatinib treatment, angiosonography reveals a hypoechoic contrast-enhanced nodule (arrow) within a mass; B, CT obtained at the same time point of (A) shows an enhanced nodule (arrow) within a mass; C, PET scan obtained at the same time point of (A) and (B) shows a small focal area of very low increased fluorodeoxyglucose uptake in the treated lesion (arrow).
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Serum VEGF levels behaved in a heterogeneous manner, but two cases with higher pretreatment serum VEGF levels showed early decreasing levels. Moreover, the classical pattern of recurrence-only was correspondent to increased serum VEGF levels (Fig. 5).
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Fig. 5. Serum levels of VEGF in 10 GIST patients with longitudinally taken serum samples. Two patients achieved a classical progressive disease with both regrowth of preexisting lesions and new sites of disease (continuous black line): an increase of serum VEGF level was evident in both cases at progression. Two other patients showed a new pattern of progressive disease with a nodule within a mass only (intermittent black line): a clear increase of serum VEGF level was not evident. In the figure, when progressive disease was clinically evident is shown with a bold point. After first progression, in two cases, the dose of imatinib was increased to 800 mg/d with further progression with the same radiological pattern of the first. Arrow indicates the serum VEGF level spike coupled with classical progressive disease following a 3-week interruption of imatinib treatment because of severe asthenia in an 86-year-old patient. In two patients with higher pretreatment serum VEGF levels, an early reduction in serum VEGF levels was observed as early as 1 week: continuous (n = 1) and intermittent line (n = 1).
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In the single case receiving strict angiosonographic evaluation, a reduction in tumor vascularization was observed as early as 2 weeks, but standardized tumor response based on CT was reported only after 9 months. Liver subcentimetric metastases were better depicted with angiosonography.
In the nine additional patients in follow-up after GIST complete resection, 21 CT and angiosonography were done at the same time points. No difference was observed in the detection of disease recurrence in two patients.
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Discussion
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The early experience with imatinib in GIST patients involved classical anatomic imaging methods for tumor response assessment. Validated response criteria (WHO, Southwest Oncology Group, and Response Evaluation Criteria in Solid Tumors) were used, but these methods are validated for other diseases with classical antiproliferative agents. Angiosonography with a second-generation contrast agent (BR1) is a simple, noninvasive, and reproducible imaging technique, which represents a new method of assessing changes in tumor vascularity.
The results of this preliminary study show that angiosonography improved the display of tumor vascularity as well as the accuracy in identifying reduction in tumor vascularization. Because the number of the examined cases was relatively low, general predictions of therapeutic effects must be discussed with caution. It is very likely that an initial high vascularization and a strong reduction of tumor perfusion under treatment are correlated with the subsequent imatinib-related tumor size reduction. However, angiosonography showed an evident reduction in tumor vascularization in the cases achieving long-term stable disease based on CT according to standardized criteria. The reduction of tumor perfusion reported at angiosonography correlated with the pseudocystic appearance which can be seen on post-contrast CT during imatinib treatment. The effective overall response rate to imatinib treatment in GISTs might be higher than reported with standard anatomic imaging, according to standardized criteria.
A new "nodule(s) within a mass" pattern of recurrence after response to imatinib has been recently described in the literature (7). In our series, two patients presented this pattern of recurrence, with no difference observed in the detection between angiosonography and CT.
Importantly, a reduction in tumor vascularization observed before a reduction in tumor size, as assessed through standardized criteria, coupled with the observation that the perfusion is mainly reduced in the central part of the treated tumors is in line with recent studies monitoring antiangiogenic and antivascular therapy with functional imaging (8). A reduction in serum VEGF levels was observed as early as 1 week in the two cases with higher pretreatment serum VEGF levels (Fig. 5). Imatinib-mediated antiangiogenic and/or antivascular properties have been shown in experimental models and in vivo in chronic myelogenous leukemia, neuroblastoma, and prostate cancer (9–14). Imatinib could induce antiangiogenic and/or antivascular effects in GIST, possibly through an angiogenesis-dependent mechanism involving the downstream cascade of KIT in the tumor cells and/or platelet-derived growth factor receptors in the endothelial tumor cells and/or an antimigratory and antiproliferative effect upon smooth muscle cells needed to surround and stabilize a nascent tumor vessel (11, 15). This effect could be easily monitored with angiosonography.
A translation research interaction between radiological findings and biological/clinical studies could be suggested. The close relation between clinical outcome and the findings on angiosonography indicates that such scanning might be a useful complement to standard anatomic imaging for monitoring the therapeutic effect of imatinib in patients with metastatic GIST. Moreover, patterns of tumor response to imatinib in GIST should be described through new criteria which should in part differ from those conventionally used for cytotoxic drugs.
Large studies are warranted to compare angiosonography with standard anatomic imaging (CT or magnetic resonance) and metabolic functional imaging (fluorodeoxyglucose-PET) for monitoring the therapeutic effect of imatinib in patients with metastatic GIST and the follow-up of patients after GIST complete resection.
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Footnotes
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Grant support: Istituto Oncologico Romagnolo, Forlì, Italy.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: Presented at the 16th European Organization for Research and Treatment of Cancer-National Cancer Institute-AACR Symposium on "Molecular Targets and Cancer Therapeutics", Geneva, Switzerland, September 28 to October 1, 2004.
Received 10/ 6/04;
revised 5/25/05;
accepted 6/ 3/05.
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References
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- Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 2004;364:1127–34.
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- Schneider M, Arditi M, Barrau M, et al. BR1: a new ultrasonographic contrast agent based on sulfur hexafluoride-filled microbubbles. Invest Radiol 1995;30:451–7.
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Abstract
Patients and Methods
