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© 2002 American Society for Clinical Oncology Effects of 5,6-Dimethylxanthenone-4-Acetic Acid on Human Tumor Microcirculation Assessed by Dynamic Contrast-Enhanced Magnetic Resonance ImagingByFrom the Department of Medical Oncology and Paul Strickland Scanner Centre, Mount Vernon Hospital, Northwood, and Cancer Research Campaign, Drug Development Office, Cambridge Terrace, London, United Kingdom, and Department of Oncology, Waikato Hospital, Hamilton, and Department of Clinical Oncology, Auckland Hospital and Auckland Radiology Group, Auckland, New Zealand. Address reprint requests to Gordon J.S. Rustin, MD, Department of Oncology, Mount Vernon Hospital, Rickmansworth Rd, Northwood, Middlesex HA6 2RN, United Kingdom; email: rustin{at}mtvern.co.uk
PURPOSE: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) causes vascular shutdown in preclinical models. Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) studies were performed in the phase I trials to examine changes related to blood flow and permeability in tumor and muscle. PATIENTS AND METHODS: Sixteen patients treated with DMXAA from 500 to 4,900 mg/m2 had DCE-MRI examinations before and after treatment. The maximum gradient, the maximum enhancement, and the area under the signal-intensity–time curve (AUC) over the first 90 seconds were calculated for each pixel in regions of interest (ROIs) in muscle and tumor, and the median value for each ROI was obtained. Changes after treatment were compared with 95% limits of agreement for an individual and for groups using data from our reproducibility study. RESULTS: Nine of 16 patients had significant reductions in AUC 24 hours after the first dose of DMXAA, and eight of 11 patients had reductions of up to 66% in AUC 24 hours after the last dose. Mean reductions in gradient, enhancement, and AUC were 25%, 18%, and 31%, respectively, 24 hours after the last dose, significantly greater than the 95% limits of change for a group of 11 patients. Enhancement and AUC in muscle 24 hours after the first dose were significantly reduced, but no significant changes were seen 24 hours after the last dose. CONCLUSION: DMXAA significantly reduces DCE-MRI parameters related to tumor blood flow, over a wide dose range, consistent with the reported tumor vascular targeting activity. Further clinical evaluation of DMXAA is warranted.
5,6-DIMETHYLXANTHENONE-4-acetic acid (DMXAA) has been shown to have selective tumor vascular targeting activity in vivo, producing vascular shutdown, reductions in tumor blood flow, and hemorrhagic necrosis.1,2 It is a more potent derivative of flavone acetic acid (FAA),2,3 and although FAA and DMXAA have little direct cytotoxicity in vitro, they have antitumor activity against a range of transplantable murine tumors with established vasculatures.4-7 Both drugs also stimulate immune responses and cytokine release.8-11 The vascular effects that occur within a few hours of treatment appear to be related to production of tumor necrosis factor-alpha (TNF-  ), as antibodies to TNF- prevent vascular shutdown.12 Antitumor effects of DMXAA correlate well with TNF- production across a series of DMXAA analogs,13 and it has been shown that intratumoral levels of TNF- rather than serum levels are important in determining both vascular shutdown and antitumor activity.14-16 FAA failed to show any antitumor activity in humans in phase I and II trials.17-22 This was thought to be due to a species-specific difference in the ability to induce TNF-, as FAA is unable to induce TNF- in human mononuclear cell lines in contrast to its activity in murine cell lines.23 DMXAA, however, induces TNF- in cell lines from both humans and mice.23
There is increasing awareness of the need to obtain evidence of drug activity by the use of surrogate markers of the biologic mechanism of action during early clinical trials, in addition to determining the pharmacokinetics, toxicity profile, and maximum-tolerated dose. The Cancer Research Campaign (CRC) conducted two phase I trials of DMXAA, in the United Kingdom (UK) and in New Zealand (NZ). Two schedules were studied, as TNF- DCE-MRI is a noninvasive technique, which yields parameters related to tissue perfusion and permeability.24-29 The paramagnetic contrast agent gadopentetate dimeglumine (Gd-DTPA) is injected as a rapid intravenous bolus, and as it passes through tissues it diffuses out of the blood vessels into the extravascular extracellular space. The signal intensity on T1-weighted images increases as the concentration of Gd-DTPA in the extracellular space increases.28-31 These changes in signal intensity are recorded by serial images acquired before, during, and after the injection. Relative changes in semiquantitative parameters such as the gradient of the signal-intensity–time curve, the maximum increase in signal intensity normalized to baseline signal intensity (enhancement), and the area under the initial part of the curve (AUC) can be examined, which are indirectly related to changes in the physiologic end points of interest: tissue perfusion, vascular permeability, and vessel surface area.24,27,32-34 A reproducibility study of this technique in humans has been performed at Mount Vernon Hospital, which defined the limits of change in these DCE-MRI parameters that might occur spontaneously between two examinations performed 5 days apart.35 Thus, the aim of this study was to determine whether significant changes in DCE-MRI parameters greater than these limits of spontaneous change were measurable in tumor and muscle after DMXAA treatment. Reductions in these parameters in tumor would be expected if this drug were acting as a tumor vascular targeting agent in humans.
The study protocol was approved by the local ethics committees, and all patients gave written informed consent to enter the imaging part of the trial. In the UK study, patients treated at or above 500 mg/m2 at Mount Vernon Hospital had DCE-MRI examinations performed within 1 week before the first dose, 4 to 6 hours after the first dose, 24 hours after the first dose, and 24 hours after the final dose of DMXAA. After the first five patients were examined, it was apparent that changes seen at 24 hours were at least as great as those at 4 to 6 hours. It was also appreciated that data were required to determine the reproducibility of the technique. Subsequently, patients had two pretreatment examinations in the week before the first dose, and 24 hours after the first and last dose. Two patients who were assessed in the NZ trial had DCE-MRI examinations within a day before, and 24 hours after each of the initial two doses of DMXAA. The first five UK studies were performed on a 1.9-T Elscint scanner (Haifa, Israel) and subsequent studies on a 1.5-T system, Magnetom Symphony (Siemens Medical Systems, Erlangen, Germany), using a body coil. The two NZ patients studies were performed on a 1.5-T LX Highspeed (General Electric Medical Systems, Milwaukee, WI). At each imaging session in the UK study, anatomic T1-weighted and T2-weighted images of all tumor sites were first obtained. A marker lesion (> 2 cm in size) was chosen for the DCE-MRI examination. Care was taken to reposition the patient in exactly the same position on subsequent visits in order to obtain the same anatomic slice location. Between three and five slices were chosen up to 8 cm apart, with one slice through the center of the marker lesion and another positioned to image a region containing skeletal muscle. A dynamic series of 30 T1-weighted spoiled gradient echo (fast low-angle shot) images was then acquired for the same slice locations, with three images before a manual bolus intravenous injection of Gd-DTPA 0.1 mmol/kg, given over 10 to 12 seconds using a standardized injection protocol. Images were acquired consecutively with no time gaps. Each set of three to five images took 11.9 seconds to acquire, and the entire sequence took 6 minutes. The imaging parameters for the T1-weighted fast low-angle shot sequence were an echo time of 9 to 10 msec, repetition time of 80 msec, 70° flip angle, and 10-mm slice width. The procedures in the NZ study were similar, with four 10-mm slices chosen and then 30 dynamic images being taken at 17-second intervals with injection of Gd-DTPA over 10 seconds after the third image. Imaging parameters for the spoiled gradient echo sequence were echo time of 9 msec, repetition time of 80 msec, flip angle of 70°, and 10-mm slice width. Images were transferred to a Sun workstation (Sparc 10; Sun Microsystems, Mountain View, CA), and analyzed using in-house software and Analyze software (Mayo Foundation, Rochester, MN). Using information from anatomic T1- or T2-weighted images and postcontrast T1 images, regions of interest (ROIs) were carefully drawn around tumor edges, including the entire tumor where possible but excluding pulsatility artifacts from blood vessels and susceptibility artifacts from adjacent bowel. ROIs were also drawn for areas of skeletal muscle (usually paraspinal muscle). For examinations performed within a short time interval (eg, before and 24 hours after the first dose), identical ROIs were used for each. In cases where the tumor had changed in size by the final examination, a new ROI was drawn to encompass the entire tumor. In the NZ study, an elliptical ROI was carefully drawn around both the tumor and a region of skeletal muscle using the Siemens Functools software, which also calculated mean pixel intensities within each ROI. Two trained observers (A.R.P. and N.J.T.) working in consensus evaluated the patterns of enhancement within each ROI by inspection of subtraction images obtained 90 seconds after injection and by reviewing maximum gradient pixel maps (see below). This evaluation was performed on the examinations acquired 24 hours and 5 weeks after commencing treatment The maximum gradient (G) of the signal intensity time curve and the enhancement (E) were calculated as follows:
where St is the signal intensity at time t, and S0 is the baseline signal intensity, taken as the mean value from the first three images. G is therefore a measure of the rate of uptake of Gd-DTPA into the tissue, and E is a measure of the maximal accumulation of Gd-DTPA in the tissue over the time course of the examination. Normalization to the baseline signal intensity therefore corrects for potential variation in instrument gain. A further check for possible changes in gain was performed by monitoring the signal intensity throughout the image acquisition sequence in a region of noise and in regions of interest in phantoms of known T1 that were placed in the field of view. The time to maximum enhancement was typically between 200 and 310 seconds, and the time of maximum gradient was between 36 and 48 seconds after contrast injection was started. For a freely diffusible tracer, the rate of uptake into a tissue is determined by the blood flow to the tissue.36 For a tracer confined to the vascular compartment, the accumulation of the tracer in the tissue gives a measure of the vascular volume.31 As Gd-DTPA is neither freely diffusible nor a blood pool marker, use of these semiquantitative parameters does not give a pure measure of tissue blood flow or of vascular volume, as the rate of uptake of Gd-DTPA into the tissue is also dependent on vessel permeability and surface area.37 In addition, individual arterial input functions were not obtained. As the parameter gradient is sensitive to changes in the arterial input function, alterations in cardiac output or injection time will affect tumor gradient values. AUC was therefore also calculated as the area under the signal-intensity–time curve over the first 90 seconds after the arrival of the bolus, as recommended by Evelhoch38 when an individual arterial input is not obtained. Furthermore, these parameters were calculated using signal intensities rather than Gd-DTPA concentrations. The increase in signal intensity can be affected by the initial tissue T1 as well as by the machine gains. All parameters were calculated with normalization to baseline to reduce the effect of different machine gains, and comparisons were performed for the same tissues at different time points. Despite these limitations, the semiquantitative parameters described above have been demonstrated to produce good correlation with a method for measuring absolute blood flow changes after treatment with a vascular targeting agent in a rat model.39 However, the size of treatment effect may be underestimated, particularly for the gradient parameter. AUC gave the best estimate of the size of treatment effect from these three parameters (R. Maxwell, PhD, personal communication, July 2001). Median values for the distribution of DCE-MRI parameters in each ROI were obtained for each examination, as the distributions of parameters were skewed. In our reproducibility study,35 we have established that the variability of the parameters used here was not dependent on the initial value of the parameter, and have calculated the size of changes needed for statistical significance in individuals, and in groups of patients. Two statistics from that study have been applied here—the repeatability or 95% limit of agreement, which gives the value of the absolute change in a parameter that might occur in an individual patient spontaneously. Any change greater than this value in an individual patient is considered statistically significant. The 95% limit of agreement for a group of n patients can be determined from the value of the mean squared differences (dsd) derived from the reproducibility study using the following formula:
The values of dsd for gradient, enhancement, and AUC were 0.49 (34%), 0.10 (13%), and 0.11 (17%), respectively, for tumor; and 0.18 (40%), 0.04 (16%), and 0.07 (24%), respectively, for muscle from a group of 16 patients (arbitrary units).35 The mean change in parameters at 4 hours and 24 hours after the first dose of DMXAA and after the sixth dose were compared with this group 95% limit of agreement to determine statistical significance. Where two pretreatment examinations were performed, the mean value of the parameter from the two examinations was taken as the baseline value.
Patient characteristics are listed in Table 1. The range of tumor types reflects the need to select tumor masses that did not move with respiration. Pretreatment DCE-MRI examinations were performed in 16 patients. Posttreatment DCE-MRI examinations were performed on six patients 4 hours after the first dose of DMXAA, on 16 patients 24 hours after the first dose, and on 11 patients 24 hours after the last dose of DMXAA. The pretreatment gradient, enhancement, and AUC values for tumors are plotted in Fig 1, where it can be seen that there was a greater than five-fold variation in gradient and enhancement values. There was a seven-fold variation in tumor AUC between the UK patients. The AUC values for the two NZ patients are much higher than any of the UK patients, which may reflect differences in the machine gain and scaling factors between the two imaging sites. Mean values for tumor ROIs are listed in Table 2.
Figure 2 illustrates the absolute changes in gradient, enhancement, and AUC for tumor ROIs. The 95% limit of agreement for an individual (repeatability value) derived from our reproducibility study is also shown.35 Relative changes in tumor gradient, enhancement, and AUC are shown in Fig 3. Five patients had reductions in gradient 24 hours after the first dose greater than the 95% limit of agreement. Nine of 16 patients had reductions in enhancement 24 hours after the first or last dose of DMXAA greater than the 95% limit of agreement. A reduction in AUC greater than the 95% limit of agreement was seen in nine of 16 patients 24 hours after the first dose of DMXAA and in eight of 11 patients 24 hours after the last dose, with a total of 12 patients having a significant reduction in AUC at one of these times. Figure 4 illustrates parameter maps for gradient, enhancement, and AUC in patient no. 2 with metastatic renal carcinoma treated at 650 mg/m2. The images demonstrate marked intratumor heterogeneity in all parameters. The posttreatment images demonstrate a clear reduction in all parameters after treatment, which is especially marked in the central area of the tumor. This observation of a greater effect in the central rather than peripheral part of the tumor in patient no. 2 is a frequent pattern in tumors treated with DMXAA, confirmed by two trained observers working in consensus. At the 24-hour and 5-week time points, visible reductions in enhancement were seen on the maximum gradient pixel maps in seven and six of 13 UK patients, respectively. A greater reduction in the center than at the edge of marker lesions was seen in five of these patients at each time point.
The pretreatment value of gradient was significantly correlated with relative change 24 hours after the first dose of DMXAA (r = -.58, P = .02) (Fig 5). There was no obvious dose response for reduction in any parameter over the doses tested (500 to 4,900 mg/m2).
The pretreatment gradient, enhancement, and AUC mean values for muscle are listed in Table 2. The values for all these parameters were lower in muscle than in tumor. The absolute and relative changes in gradient, enhancement, and AUC for muscle are illustrated in Figs 6 and 7. No patients had a reduction in muscle gradient greater than the 95% limits of agreement, but three patients had a reduction greater than this limit for enhancement, and four patients had significant reductions in AUC. As resting skeletal muscle has relatively low blood flow, the absolute changes seen were smaller for muscle than for tumors, but there were larger fluctuations in relative changes. Figures 6 and 7 also demonstrate that in muscle there does not appear to be a dose response across the dose range examined.
Mean changes for the group relative to the pretreatment values were determined and are plotted in Fig 8. The NZ data were excluded from this analysis, as the pretreatment parameter values were much greater than the UK data, and might have biased the analysis. The 95% confidence intervals for change for the number of patients at each dose level are also shown. Any change greater than this is significant at the 5% level.
Significant reductions were seen in tumor kinetic parameters at all time points except 4 hours after the first dose of DMXAA for gradient. The mean reductions (± SE) in gradient, enhancement, and AUC in tumors 24 hours after the first dose of DMXAA were 0.51 ± 0.11, 0.17 ± 0.06, and 0.22 ± 0.05, respectively (arbitrary units). These correspond to mean 21%, 14%, and 21% reductions, respectively. At 24 hours after the last dose of DMXAA, there were significant mean reductions in all three parameters of 0.60 ± 0.13, 0.22 ± 0.07, and 0.33 ± 0.08, respectively, representing reductions of 25%, 18%, and 31%, respectively. There were significant reductions in gradient (0.17 [29%]) for muscle ROIs at 4 hours, in enhancement at 4 and 24 hours (0.06 [19%] and 0.04 [11%]), and in AUC at 24 hours (0.07 [18%]) after the first DMXAA treatment, but no significant change in any parameter after the sixth dose.
These data demonstrate that DMXAA reduces the DCE-MRI parameters gradient, enhancement, and AUC in human tumors across a wide range of dose levels. These parameters are indirect measures of a combination of tissue perfusion, vessel permeability, and vessel surface area,24,27,32 and these results illustrate that DCE-MRI can provide a noninvasive indicator of biologic activity in this class of vascular targeting drugs.
We have previously demonstrated that the DCE-MRI technique used at Mount Vernon Hospital has reasonable reproducibility. Using data from that study, the change in gradient, enhancement, and AUC that might occur in tumors within a week in the absence of treatment for a group of 14 patients is 0.24 (17%), 0.05 (6%), and 0.06 (8%), respectively.35 The mean reductions in parameters of all patients treated at
In another study, the changes in DCE-MRI parameters have been compared with actual changes in absolute blood flow measured using a radiotracer technique in a rat tumor model treated with the vascular targeting agent combretastatin A4 phosphate (CA4P). The DCE-MRI protocol used in rats was the same as that used in this study, with smaller slice thickness, and fields of view as required by the smaller tumors. When the gradient from the signal-intensity–time curve was used as a measure of flow, the correlation with radiotracer measurements of absolute blood flow was good (r = .97, P = .002). However, the reduction in gradient and AUC in response to treatment with 10 mg/kg CA4P was 20% and 59%, respectively, at 1 hour after treatment, a dose that produces 91% reduction in blood flow measured with radiotracer at this time (R. Maxwell, PhD, personal communication, July 2001). This underestimation of treatment effect may be due in part to the nature of the contrast agent used, which is neither freely diffusible nor a blood pool marker. Measurements of gradient will therefore reflect changes in permeability vessel surface area and perfusion to varying extents. Permeability within the tumor vessels may well increase after DMXAA treatment, as TNF- A common feature of vascular targeting agents in preclinical models is the preservation of viable cells in the rim of tumors, even when extensive vascular shutdown and hemorrhagic necrosis is seen, and these cells subsequently repopulate the tumor.49-52 Therefore, clinical responses when antivascular agents such as DMXAA are used as single agents would not be anticipated. Indeed, in each phase I trial of DMXAA, only one unconfirmed response was seen. The tendency of DMXAA to have a greater effect on tumor blood flow in the central part of tumors was confirmed in this study by two trained observers. A more quantitative method for assessment of tumor heterogeneity in response is being developed using histogram analysis. The likely place for drugs with this novel mechanism of action is therefore in combination with other therapeutic modalities, such as cytotoxic drugs, immunomodulatory agents, or radiation therapy. Several groups have demonstrated synergistic activity of DMXAA in such combinations in preclinical models.16,53-57 In particular, Pedley et al58 have demonstrated cure of human colorectal tumor xenografts in mice treated with a combination of DMXAA and radioimmunotherapy at a dose of DMXAA that produces no growth delay as a single agent. This pattern of limited antitumor effect after use alone, but better than additive activity when used in combination with other anticancer agents, is also seen with another vascular targeting agent, CA4P.52 Despite the likelihood of underestimation of actual blood flow reduction after DMXAA treatment, the reduction in DCE-MRI parameters seen in some patients in the phase I trials of DMXAA is greater than the 40% reduction in tumor perfusion seen 24 hours after a dose of CA4P 100 mg/kg in mice.52 This level of blood flow reduction is insufficient to produce tumor growth delay when used alone, but nevertheless CA4P enhances the antitumor effect when used in combination with cisplatin chemotherapy or radiotherapy.52 In conclusion, the DCE-MRI data demonstrate reductions in tumor gradient, enhancement, and AUC seen across a wide spectrum of well-tolerated dose levels in human tumors. These data are consistent with the reported vascular targeting activity of DMXAA in preclinical models, and provide encouragement for the further development of this drug, particularly for combination with chemotherapy agents, radioimmunotherapy, or radiation. This study also highlights the importance of assessing therapies with novel modes of action by examining biologic end points that are directly or indirectly related to mechanisms of drug action, in addition to the traditional end points of toxicity and response.
Supported by The Community Fund, London, United Kingdom. The Cancer Research Campaign funded and organized the phase I 5,6-dimethylxanthenone-4-acetic acid trial, the Cancer Treatment and Research Trust funded the magnetic resonance imaging examinations. We thank Jane Boxall, Research Sister, for help with the care of the patients on this study.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
500 mg/m2 were greater than these values, with a maximum individual reduction of more than 60% in all three parameters. Changes of parameters in skeletal muscle ROIs were only seen in a minority of patients. Mean reductions in muscle were less than those in tumor, not seen in all parameters at each time point, and there were no significant changes 24 hours after the last dose. This suggests some degree of tumor specificity for the effects of DMXAA on tissue blood flow. The methodology used cannot account for any systemic effects of the drug on cardiac output; for example, there were no significant changes in blood pressure or pulse rate at the times of the posttreatment examinations (data not shown). 
