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Experimental Studies |
1 From the Departments of Radiology (H.C.T., F.D.K., F.C., Y.N., H.B., G.M., R.H.), Experimental Radiobiology/Laboratory of Experimental Oncology (W.L.), and Pathology (E.K.V.), University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium; and Department of Radiology, Zhong Da Hospital, Southeast University, Nanjing, China (F.C.). Received October 24, 2003; revision requested January 13, 2004; final revision received May 19; accepted June 17. H.C.T. supported by a grant from the Bernese Cancer League and by the Kurt and Senta Hermann Foundation. Address correspondence to Y.N. (e-mail: yicheng.ni@med.kuleuven.ac.be).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Study protocol was approved by local ethical committee for animal care and use. Rhabdomyosarcomas implanted subcutaneously in both flanks of 17 rats were evaluated with 1.5-T MR unit by using four-channel wrist coil. Transverse T2-weighted fast spin-echo sequences, T1-weighted spin-echo sequences before and after gadodiamide administration, and transverse echo-planar diffusion-weighted MR examinations were performed before, 1 and 6 hours, and 2 and 9 days after intraperitoneal injection of vascular targeting agent (combretastatin A4 phosphate, 25 mg/kg). Apparent diffusion coefficient (ADC) was automatically calculated from diffusion-weighted MR imaging findings. These findings were compared with histopathologic results at each time point. For statistical analysis, paired Student t tests with Bonferroni correction for multiple testing were used.
RESULTS: T1-weighted images before combretastatin administration showed enhancement of solid tumor tissue but not of central necrosis. At 1 and 6 hours after combretastatin injection, enhancement of solid tissue disappeared almost completely, with exception of small peripheral rim. At 2 and 9 days after combretastatin injection, enhancement progressively reappeared in tumor periphery. ADC, however, showed decrease early after combretastatin injection ([1.26 ± 0.16]x 10–3 mm2/sec before, [1.18 ± 0.17]x 10–3 mm2/sec 1 hour after [P = .0005] and [1.08 ± 0.14]x 10–3 mm2/sec 6 hours after [P = .0007] combretastatin A4 phosphate injection), histologically corresponding to vessel congestion and vascular shutdown in periphery but no necrosis. An increase of ADC ([1.79 ± 0.13]x 10–3 mm2/sec) (P < .0001) 2 days after combretastatin A4 phosphate injection was paralleled by progressive histologic necrosis. A significant (P < .0001) decrease in ADC 9 days after treatment ([1.41 ± 0.15]x 10–3 mm2/sec) corresponded to tumor regrowth.
CONCLUSION: In addition to basic relaxation-weighted MR imaging and postgadolinium T1-weighted MR imaging to enable prompt detection of vascular shutdown, diffusion-weighted MR imaging was used to discriminate between nonperfused but viable and necrotic tumor tissues for early monitoring of therapeutic effects of vascular targeting agent.
© RSNA, 2005
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Combretastatin A4 phosphate is an antitubulin drug with inherent vascular targeting agent activity. To our knowledge, the precise mechanism of combretastatin induction of vascular shutdown is not fully understood (3,4); however, combretastatin is known to induce rapid changes in endothelial cell shape and to disrupt the endothelial cell layer and the underlying basement membranes. This leads to blood vessel congestion and loss of blood flow. Loss of oxygen and nutrient supply and impaired removal of metabolites induces cell death and consequent necrosis of the affected tumor tissue.
Combretastatin A4 phosphate has undergone phase l clinical trials (5–8). These studies showed tumor blood flow reduction in human tumors at well-tolerated doses, without persisting alteration of normal organs. Noninvasive monitoring of treatment response, including insight into typical intratumoral changes after the use of vascular targeting agents, is of major clinical importance.
Monitoring of clinical studies was performed mainly with dynamic contrast medium–enhanced magnetic resonance (MR) imaging or positron emission tomography (PET) (5,8). In addition to these modalities, experimental studies involved the use of scintigraphy, MR spectroscopy, radioactive tracer methods, and autoradiography to demonstrate early (eg, up to 24 hours) changes after combretastatin treatment (9–13).
Diffusion-weighted MR imaging is becoming more and more important in the assessment of tumors and evaluation of response during follow-up with various treatment modalities (eg, chemotherapy and radiation therapy) (14–18).
To our knowledge, there is only one study (9) in which treatment response with diffusion-weighted MR imaging after administration of combretastatin A4 phosphate was evaluated. In short-term follow-up (160 minutes after administration of combretastatin A4 phosphate), no substantial change could be observed (9). Thus, the purpose of our study was to evaluate diffusion-weighted MR imaging in monitoring response in rats after administration of the vascular targeting agent combretastatin A4 phosphate.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Experiments were performed in 17 male adult WAG/Rij rats (Iffa Credo, Brussels, Belgium) that weighed 280–300 g each. Two rhabdomyosarcoma tumors (1-mm3 pieces) were implanted subcutaneously (W.L.) in the flank region on opposite sides at the level of the kidneys. One tumor was implanted in each flank. The resultant 34 tumors had a baseline mean tumor volume of 2.34 cm3± 0.62 (range, 1.93–3.78 cm3) before treatment.
Five rats were examined during a follow-up period of 9 days after intraperitoneal administration of combretastatin A4 phosphate (Oxigene, Watertown, Mass) at a dose of 25 mg per kilogram of body weight and sacrificed thereafter. For histopathologic comparison at the intermediate time points of 1 hour, 6 hours, and 2 days after combretastatin A4 phosphate administration, three rats for each time point were sacrificed after examination with MR imaging. Three control rats underwent MR imaging before and 1 and 6 hours after intraperitoneal administration of a volume of saline identical to that of combretastatin A4 phosphate.
MR Imaging
The rats were examined with a 1.5-T whole-body MR system (Sonata; Siemens, Erlangen, Germany) with a maximum gradient capability of 40 mT/m. A four-channel phased-array wrist coil was used to obtain all MR images and allowed parallel imaging (generalized autocalibrating partially parallel acquisition, or GRAPPA, factor of two in all series). The rats were placed in the supine position in a plastic holder and connected with a mask to an anesthetic system to avoid movement. Rats were initially anesthetized with inhalation of 4% isoflurane; anesthesia was maintained with 2% isoflurane in a 20% oxygen and 80% room air mixture. The penile vein was cannulated for intravenous access.
A coronal T1-weighted spin-echo sequence was used as a localizer. Transverse T1-weighted spin-echo (repetition time msec/echo time msec, 553/15; matrix, 120 x 256) and T2-weighted turbo spin-echo sequences (5860/99; matrix, 160 x 256) were performed with a section thickness of 2 mm and an intersection gap of 0.2 mm. The field of view was 81.3 x 130.0 mm and covered both tumors entirely (20 sections).
The acquisition time was 1 minute 32 seconds for the T1-weighted sequence with two signals acquired and 1 minute 34 seconds for the T2-weighted sequence with three signals acquired.
Diffusion-weighted echo-planar imaging was performed with the following gradient factors: 0, 50, 100, 150, 200, 250, 300, 500, 750, and 1000 sec/mm2. The following parameters were used for this sequence: 3300/124; matrix, 96 x 192; number of signals acquired, four; time of acquisition, 2 minutes 35 seconds. Apparent diffusion coefficient (ADC) maps were calculated automatically. ADC is measured in square millimeters per second.
After intravenous administration of 0.2 mL of gadodiamide (Omniscan; Amersham, Oslo, Norway) (0.5 mmol/L), a transverse T1-weighted spin-echo sequence was performed, with fat saturation identical to that obtained in the precontrast study.
All sequences were performed with the same geometry to maintain comparability between the different imaging sequences.
Image Analysis
The image analysis was performed off-line at a Linux workstation by using dedicated software (Biomap; Novartis, Basel, Switzerland). In the transverse precontrast T1-weighted sequence, entire tumors were manually delineated on each section with consensus of two observers (H.C.T., 7 years of experience; F.D.K., 1 year of experience). Merging the delineations of each tumor yielded two three-dimensional regions of interest (ROIs), from which the system automatically calculated the average signal intensity of both tumors in each rat. The signal intensities of the conventional sequences were visually compared with muscle and graded as hypo-, iso-, or hyperintense. For the ADC maps, the same grading of the signal intensities was applied by comparing the center and the periphery of the tumor. The window and level settings of the display station were kept constant. This approach was chosen because ADC maps consist of absolute values.
Analysis of the diffusion-weighted MR images was performed. In the first step, ROIs of the T1-weighted images were copied to the ADC maps at each time point and manually adjusted in case of minor distortions that are sometimes visible on ADC maps and are caused by the echo-planar imaging sequence used. In the second step, several circular ROIs were placed in the periphery (defined as the outer 5 mm) and in the center (more than 8 mm from the rim) of each tumor. Again, the respective ROIs were merged to obtain one center ROI and one peripheral ROI for each tumor. For comparison purposes, a circular ROI in the back muscles was drawn on a single section and copied from the T1-weighted images to the diffusion-weighted MR images. Afterward, the ROIs of the ADC maps were copied to the corresponding original diffusion-weighted images, from which the average intensities for each b value could be obtained.
In addition, ADCs of the tumors were calculated separately for low (0, 50, and 100 sec/mm2) (ADClow) and high (500, 750, and 1000 sec/mm2) (ADChigh) b values to better differentiate the relative influence of the perfusion fraction and true diffusion.
ADCs were calculated by using a least squares solution of the following system of equations: S(i) = S0 · exp (–bi · ADC), where S(i) is the signal intensity measured on the i’th b value image, and bi is the corresponding b value. S0 is a variable estimating the exact (without noise induced by the MR measurement) signal intensity for a b value of 0 sec/mm2. To reduce influence of noise on the calculations, diffusion images with at least three different b values were used.
On the postcontrast T1-weighted images, the maximum diameter of the enhancing rim was measured in millimeters at each time point.
Histologic Analysis and Correlation with MR Imaging
After surgical excision of the tumors from the sacrificed rats at the previously mentioned time points, transsections were made in the transverse plane corresponding to the MR sections after fixation in 10% formaldehyde solution. Following paraffin embedding, 5-µm slices were stained with hematoxylin-eosin. All slices were examined by two pathologists in consensus (E.K.V. and Y.N., with 20 and 15 years of experience, respectively) by using magnification that ranged from x12.5 to x400. Tissue slices were microscopically assessed for the presence and extent of viable tumor cells and necrosis and for the status of intratumoral vasculature (eg, vessel patency, constriction, congestion, or dilatation). Thereafter, the histologic slices were compared with the corresponding spin-echo images and the ADC maps (H.C.T., W.L., E.K.V., and Y.N.). Comparison was based on viability of tumor cells versus necrosis, presence or absence of hemorrhage, and status of intratumoral vasculature at histologic analysis in relation to the enhanced versus unenhanced areas on the T1-weighted contrast material–enhanced MR images and the signal intensity on ADC maps.
Statistical Analysis
Statistical analysis was performed with Excel 9.0 (Microsoft, Seattle, Wash) and Analyse-It 1.68 (Analyse-it Software, Leeds, UK) software packages. Numeric data are reported as mean ± standard deviation.
Statistical analysis was performed by using a two-tailed paired Student t test with Bonferroni correction for multiple testing. A P value of less than .05 was considered to indicate a statistically significant difference. Retrospective power analysis was performed for all statistically significant results.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Before Combretastatin Injection
The T1-weighted images show homogeneous low signal intensity of the entire tumor; after gadodiamide administration, solid enhanced tissue with a central unenhanced area was visible (Fig 1, A1, A4). The corresponding T2-weighted images reveal slightly inhomogeneous high signal intensity of the tumors (Fig 1, A2).
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Follow-up: 2 Days after Combretastatin Injection
Two days after treatment, central signal intensity on the T1-weighted images decreased slightly (Fig 1, D1) in comparison to that of previous studies (Fig 1, B1, C1), with a small but slightly thickened peripheral enhancing rim remaining (Fig 1, D4; Fig 3). In most cases, the T2-weighted images were similar to those obtained in previous studies. The ADC maps showed inhomogeneous hyperintense tumors without differentiation of the center and periphery. The corresponding ADCs of the entire tumors increased significantly (P < .0001). The ADCs calculated from the low and high b values also increased significantly (P < .0001) (Fig 2, Table 1). The ADC of the center increased (P = .02); however, only the ADChigh increased significantly (P = .002), whereas the ADClow remained mainly unchanged (Table 2, Fig 4). The ADC of the periphery increased significantly (P < .0001) for both ADChigh and ADClow.
Histologic examination demonstrated enlargement of the necrotic area, and only a small rim of viable tissue at the outer periphery remained (Fig 3, D3).
Follow-up: 9 Days after Combretastatin Injection
Nine days after combretastatin A4 phosphate injection, the enhancing rim of the tumors thickened significantly (P < .001) (Fig 1, E4; Fig 3). The T2-weighted images showed a hyperintense center with a broad hypointense periphery. The mean ADC of the entire tumor at this time point decreased significantly compared with that measured 2 days after combretastatin A4 phosphate injection (P < .0001) (Table 1, Fig 2). The mean ADC of the center increased significantly (P = .007); however, the increase was only significant for ADClow (P = .0007) and not for ADChigh (Fig 4, Table 2). In contrast, the ADC of the periphery decreased significantly (P < .0001) for ADClow (P = .009) and ADChigh (P < .0001).
The corresponding histologic specimen revealed regrowth of solid tumor in the periphery in a centrifugal manner.
Follow-up of the solid enhancing rim is shown in the last column of Figure 1 (A4, B4, C4, D4, E4), and the corresponding measurements are shown in Figure 5.
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Retrospectively, the powers of all significant results were calculated. These ranged from .88 to 1, with the exception of one outlier, which only had a power of .67.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Intratumoral changes after this kind of treatment are important to recognize because in contrast to other anticancer therapies, such as use of cytotoxic agents and irradiation, a decrease in tumor volume is not an expected treatment response (19).
There are several requisites for an optimal imaging technique to monitor therapy response: The method should be noninvasive and quantitative, sample the entire tumor, be quick to perform, and allow repetition at frequent intervals.
Diffusion-weighted MR imaging has several potential advantages over other methods (eg, CT, PET, biopsy): It is noninvasive, without ionizing radiation exposure and the need for contrast medium administration, and it has a shorter examination time. The technique is easy to repeat, allowing close follow-up in cancer treatment. In addition, postprocessing is less time-consuming for diffusion-weighted MR imaging than for other methods (eg, dynamic contrast-enhanced MR imaging). In combination with conventional MR imaging, morphologic and physiologic changes can be assessed during the same examination.
Diffusion-weighted MR imaging allows monitoring of the entire tumor. This is very important because of the vast heterogeneity of most tumors. Tissue sampling is invasive and may not be representative of the entire tumor (20). Sampling also carries with it the inherent risks of infection, hemorrhage, and seeding along the needle track.
Diffusion-weighted MR imaging provides information about microscopic structures, such as cell density and integrity or necrosis (21). Thus, a viable tumor can be differentiated from a necrotic tumor with diffusion-weighted MR imaging (20) in contrast to conventional MR imaging.
Tissue with high cellular density shows low ADC resulting from impeded mobility of water protons by the higher amount of cell membranes (21,22), whereas necrotic tissue shows high ADC resulting from rapid diffusion of water protons as a consequence of lost membrane integrity (21). When analyzing the early effects of combretastatin A4 phosphate on tumors at 1 and 6 hours after drug administration with conventional contrast-enhanced images, the findings suggest necrosis of most parts of the previously viable tissue with the exception of a small solid rim in the periphery; however, diffusion-weighted MR imaging provides different information. Our results demonstrate that vascular shutdown appears early (1 and 6 hours) after combretastatin A4 phosphate injection, and this is only later followed by necrosis.
Thanks to the high sensitivity of diffusion-weighted MR imaging to molecular displacements in the orders of microns (three orders of magnitude less than the spatial resolution of a typical clinical MR examination), this method is very sensitive to biophysical changes related to tumors, even during their very early stages of development (23).
As a quantitative parameter of diffusion-weighted MR imaging, ADC reflects not only diffusion but also perfusion of microvessels (24). A large range of b values (b = 0, 50, 100, 150, 200, 250, 300, 500, 750, and 1000 sec/mm2) was used to calculate two different ADCs. Those with low (0, 50, and 100 sec/mm2) and those with high (500, 750, 1000 sec/mm2) b values provide different information. Previous studies have shown that for low b values (b < 100 sec/mm2), perfusion dominates diffusion by a factor of 10 (24,25). Thus, use of low and high b values in the same setting for calculation of ADC reflects contributions from both diffusion and perfusion effects, whereas a set of low b values is more weighted to the effects of perfusion. A set of high b values reduces the influence of perfusion and approximates true diffusion.
Early after treatment (1 and 6 hours), a significant decrease in the mean ADC of all tumors could be observed. This means diffusion is restricted, which can be attributed to early hemorrhage or ischemia—conditions that are not distinguishable on diffusion-weighted MR images alone (26). When analyzing the ADC of low and high b values separately, however, the decrease of the ADC of the low b values was more pronounced than the decrease of the high b values, which suggests a decrease mainly in perfusion due to vascular shutdown and probably consequent cell swelling. Furthermore, our results suggest that the most dramatic effect of combretastatin A4 phosphate on the tumor vasculature occurs within the first hour. Histologically, these findings corresponded to vessel constriction at 1 hour and vessel congestion at 6 hours. The remaining hypointense rim on the ADC map reflects a high cellular density, which represents the tumor cells still present in the histologic specimen. However, the contrast-enhanced T1-weighted images indicate almost complete disappearance of perfusion in the periphery, with only a small remaining rim suggesting peripheral extension of the necrotic area. Thus, the conventional MR images provide an incomplete assessment of the changes in the tumor microenvironment.
A slightly progressive increase in central hyperintensity on the T1-weighted series from the images obtained at 1 and 6 hours could be seen. The corresponding histologic specimen did not show hemorrhage. The central hyperintensity seen on T1-weighted images was consistent with contrast medium from the previous studies trapped in the necrotic regions. This interpretation could be substantiated by a pilot study performed in tumor-bearing rats without treatment (data not shown).
Two days after combretastatin A4 phosphate injection, the conventional contrast-enhanced T1-weighted images showed the same extent of necrosis but with a slightly thickened peripheral rim when compared with the previous images. The corresponding ADC map and values showed substantial changes, which were suggestive of tumor cell damage and consequent necrosis.
The integrity of the cell membranes is compromised by the lack of nutrients with vascular shutdown, and the fractional volume of the interstitial space increases because of apoptotic body formation and cell loss. These changes increase the mobility of free water in the damaged tissue and are reflected by an increase in the ADC. Thus, successful therapy is expected to lead to a concomitant increase in ADC, a feature indeed observed in animal and human studies (27,28).
A rim of viable cells at the periphery is often observed after treatment with combretastatin A4 phosphate (29). There is a tendency of blood flow to recover more quickly in the peripheral tumor regions than in the central regions (13). The response of the peripheral vessels to combretastatin A4 phosphate treatment is reduced; the exact mechanism is unknown (12). This limits the effectiveness of combretastatin A4 phosphate administration and results in rapid regrowth of tumors after treatment (3).
The increase of ADClow 2 days after treatment may reflect recovering blood flow in the tumor periphery. This rim can be targeted with adjuvant conventional cytotoxic approaches or radiation therapy (30–33).
The decrease of the entire tumor ADC from 2-day follow-up to 9-day follow-up after combretastatin A4 phosphate injection reflects tumor recurrence, a finding that can also be observed on the contrast-enhanced T1-weighted images with a large enhancing rim in the tumor periphery. This information cannot be obtained with conventional imaging methods without use of gadolinium.
Changes in ADC are more pronounced in the tumor periphery than in the center. Thus, the ADC of the entire tumor can be used for follow-up to provide information on the microenvironment of the entire tumor. The averaged values comprised both the peripheral and the central zone, and they are less discriminating over time; however, they still appropriately reflect changes in the tumor. Measuring ADC over the entire tumor has the further advantage of being easier to perform; also, selection bias of the investigator can be excluded when determining the different areas within the tumor.
Our findings of rapid reduction of tumor blood flow after combretastatin A4 phosphate injection corroborate findings of several studies in which other techniques were used (11,12,13,30,34); however, information pertaining to cellular integrity is only provided by diffusion-weighted MR imaging.
In contrast to most other experimental studies (11,12,13,34) in which high-field MR imaging is used, our experiments were performed with a clinical 1.5-T MR unit. As these machines allow parallel imaging, the resulting shorter examination time may be helpful in clinical trials.
A potential shortcoming of this study is the slight anatomic distortion present in the diffusion-weighted MR images and ADC maps when compared with the T1- and T2-weighted spin-echo images, which is caused by susceptibility effects in echo-planar imaging. This may reduce appreciation of intratumoral tissue heterogeneity with diffusion-weighted MR imaging. Also, as the number of time points investigated after injection of combretastatin A4 phosphate was limited, this study does not allow us to exactly determine the time point at which the tumor tissue converts from nonperfused but viable tissue to necrotic tissue.
Practical application: Diffusion-weighted MR imaging allows radiologists to detect and quantify intratumoral changes noninvasively after administration of a vascular targeting agent. In addition to basic relaxation-weighted MR imaging and postgadolinium T1-weighted MR imaging to promptly depict vascular shutdown, diffusion-weighted MR imaging was used to discriminate between nonperfused but viable tissue and necrotic tumor tissue for early monitoring of the therapeutic effects of a vascular targeting agent. Thus, it is a promising tool for monitoring the effects of such an agent.
Improved specificity of tumor tissue characterization would be a better guide to the care of patients with malignant tumors. It could potentially be used to predict treatment outcome and help radiologists make decisions about different treatment options.
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FOOTNOTES |
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Abbreviations: ADC = apparent diffusion coefficient, ROI = region of interest
Authors stated no financial relationship to disclose.
Author contributions: Guarantors of integrity of entire study, G.M., R.H., W.L., H.C.T., Y.N.; study concepts, H.C.T., G.M., F.D.K., Y.N.; study design, H.C.T., F.D.K., G.M., W.L., H.B., Y.N.; literature research, H.C.T., W.L.; experimental studies, H.C.T., F.D.K., F.C., Y.N., W.L., H.B.; data acquisition, H.C.T., F.D.K., F.C., Y.N., W.L., H.B.; data analysis/interpretation, H.C.T., F.D.K., E.K.V., W.L., Y.N.; statistical analysis, F.D.K.; manuscript preparation, H.C.T., F.D.K., Y.N.; manuscript definition of intellectual content, H.C.T., F.D.K., R.H., G.M., W.L., Y.N.; manuscript editing, H.C.T., F.D.K., R.H., W.L., Y.N.; manuscript revision/review, H.C.T., F.D.K., R.H., Y.N.; manuscript final version approval, all authors
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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