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Originally published as JCO Early Release 10.1200/JCO.2003.05.186 on June 13 2003 © 2003 American Society for Clinical Oncology Assessment of Pharmacodynamic Vascular Response in a Phase I Trial of Combretastatin A4 Phosphate
From the Cancer Research United Kingdom Positron Emission Tomography Oncology Group, Medical Research Council Cyclotron Unit, Hammersmith Hospital; and Drug Development Office, Cancer Research United Kingdom, London, United Kingdom. Address reprint requests to: Pat Price, MD, Wolfson Molecular Imaging Centre, Academic Department of Radiation Oncology, Christie Hospital, Wilmslow Road, Manchester M20 4BX, United Kingdom; email: Anne.Mason{at}man.ac.uk.
Purpose: Clinical evaluation of novel agents that target tumor blood vessels requires pharmacodynamic end points that measure vascular damage. Positron emission tomography (PET) was used to measure the effects of the vascular targeting agent combretastatin A4 phosphate (CA4P) on tumor and normal tissue perfusion and blood volume. Patients and Methods: Patients with advanced solid tumors were enrolled onto part of a phase I, accelerated-titration, dose-escalation study. The effects of 5 to 114 mg/m2 CA4P on tumor, spleen, and kidney were investigated. Tissue perfusion was measured using oxygen-15 (15O)–labeled water and blood volume was measured using 15O-labeled carbon monoxide (C15O). Scans were performed immediately before, and 30 minutes and 24 hours after the first infusion of each dose level of CA4P. All statistical tests were two sided.
Results: PET data were obtained for 13 patients with intrapatient dose escalation. Significant dose-dependent reductions were seen in tumor perfusion 30 minutes after CA4P administration (mean change, -49% at Conclusion: CA4P produces rapid changes in the vasculature of human tumors that can be assessed using PET measurements of tumor perfusion.
TO SUPPORT continual growth, there is a fundamental requirement for any solid tumor greater than 1 to 2 mm in diameter to develop a vasculature.1 This process of angiogenesis is achieved by tumor cell release of growth factors that stimulate endothelial cell proliferation and migration.2 Increasing knowledge of the molecular regulation of angiogenesis has stimulated drug development in oncology that is focused on the discovery of antiangiogenic agents.1 Although vascular targeting agents are often grouped with antiangiogenic approaches, the rationale behind the development of these agents is different. Rather than aiming to prevent the growth of new blood vessels, vascular targeting agents aim to exploit differences between established tumor and normal tissue endothelia, and produce a rapid shutdown of tumor blood vessels.3 The resulting ischemia can lead to extensive tumor cell death in areas that are often resistant to conventional anticancer treatments. A number of drugs can selectively and irreversibly damage the vasculature of experimental tumors.4 Although this is the case for some clinically used tubulin-binding agents (eg, vincristine and vinblastine), the antivascular effects are only seen at doses approaching their maximum-tolerated dose (MTD), and are associated with significant morbidity.3,5 In contrast, combretastatin A4 phosphate (CA4P), one of the most potent of a new group of tubulin-binding agents,6–8 can exert antivascular effects at doses well below its MTD in animals.9 CA4P has a concentration-dependent cytotoxicity in vitro with much greater activity toward proliferating versus quiescent endothelial cells.9 In experimental models CA4P was shown to cause the rapid and extensive shutdown of tumor blood flow,10 increased tumor vascular resistance,11 and decreased red cell velocity.12 A rapid increase in vascular permeability was measured within minutes of treatment with CA4P,13 and the differences in experimental tumor response to CA4P have been shown to correlate positively with prior magnetic resonance imaging (MRI) measurements relating to tumor vascular permeability.14 Although vascular targeting agents can exert both antivascular and antimitotic effects, they are identified on the basis of a superior therapeutic index for their vascular effects.3,5 They may not, therefore, have the typical side effects of antiproliferative chemotherapeutic drugs. It is believed that this lack of conventional morbidity may hamper studies to determine dose and schedule of administration, and it is recognized that finding the optimum dose for therapeutic gain may require pharmacodynamic end points that aid delineation of functional damage to the tumor vasculature. It has been suggested that clinical studies must demonstrate that antiangiogenic agents affect tumor vasculature, and phase I trials should include built-in surrogate end points.15 This statement applies also to vascular targeting agents. Trials of new antiangiogenic agents now include the measurement of surrogate end points such as plasma markers of angiogenesis16 and dynamic contrast enhanced MRI.17 Positron emission tomography (PET) has potential as a noninvasive imaging modality for measuring the effects of antitumor agents on tumor vasculature. It is a sensitive method for quantifying physiologic and metabolic processes in vivo. Methods of quantifying tissue perfusion using oxygen-15 (15O)–labeled tracers have been well validated in both the brain and myocardium.18 Although there are fewer published studies in human tumors, the range of tumor perfusion values measured in cerebral, pancreatic, and hepatic tumors corresponds with that obtained using non-PET methodology.18 To date little work has been published on the use of PET to measure vascular response to anticancer therapy. A small study in two patients with hepatic tumors measured changes in blood flow before and after administration of angiotensin II.19 In addition, the measurement of blood volume changes in response to thalidomide and blood flow changes in response to endostatin have been reported in abstract form only.20,21 This article describes the use of 15O-labeled water (H215O) and carbon monoxide (C15O) to measure tumor and normal tissue perfusion, and blood volume before and after the administration of the vascular targeting agent CA4P. The aim of the work was to assess the effects of CA4P on tumor and normal tissue vasculature using PET, establish the dose at which these effects occurred, and determine the optimal biologic dose for phase II evaluation. The hypothesis behind the study was that CA4P would produce rapid changes in tumor vasculature that could be detected using PET measurements of tumor perfusion.
Study Design Patients were enrolled onto part of a two-center, phase I, dose-escalation study conducted under the auspices of the Cancer Research United Kingdom Phase I/II Clinical Trials Committee.22 Approval was obtained from the local research ethics approval committees of the Hammersmith Hospital (London, United Kingdom) and Mount Vernon Hospital (Middlesex, United Kingdom), and permission to administer radioactive tracers at the Hammersmith Hospital was given by the Administration of Radioactive Substances Advisory Committee of the United Kingdom. Written informed consent was obtained from all patients before entry onto the study. Eligible patients were  18 years old with a World Health Organization performance status  2 and histologically confirmed cancer not amenable to any standard curative therapy or refractory to conventional therapy. The inclusion and exclusion criteria have been described in detail elsewhere.22 An integral part of the study design was an enrollment requirement for tumors suitable for either MRI (Mount Vernon Hospital) or PET (Hammersmith Hospital) scanning. PET requirements were for a tumor 3 cm that was visible using computed tomography (CT). For the patients included in this report, the experimental plan was to perform PET scans immediately before drug administration, and 30 minutes and 24 hours after the completion of the CA4P infusion in every patient and at each dose level studied.
Combretastatin Administration
PET Data Acquisition Patients were cannulated with an arterial line in the radial artery for blood sampling. An intravenous line was inserted into an accessible vein in the other arm for injection of CA4P and H215O. Imaging was performed on an ECAT 931–08/12 scanner (CTI/Siemens, Knoxville, TN) that allowed the simultaneous measurement of 15 transaxial slices in 0.65-cm-thick slices covering a 10.8-cm axial field of view. Patient position was centered according to the tumor location identified from a recent CT scan. A 20-minute transmission scan was given first and used for attenuation correction. Patients then inhaled 3 MBq/mL C15O through a loose-fitting mask at a rate of 500 mL/min for 6 minutes. Two minutes after the end of C15O administration, a 6-minute emission scan was performed. Discrete blood samples were taken at 0, 2, 4, and 6 minutes to measure blood radioactivity. A second emission scan was then performed starting approximately 30 seconds before the patient received a bolus infusion of 600 MBq H215O over 20 seconds at a rate of 10 mL/min followed by a 2-minute saline flush. During the scan continuous arterial blood sampling was carried out using an online bismuth germanate oxide detector and an automated pump at a rate of 5 mL/min to measure the arterial input function.23 A discrete sample also was taken at the completion of the scan for cross-calibration of the continuous blood data. While the patient was positioned on the scanner, he or she received CA4P. After the 10-minute drug infusion, patients were observed for 30 minutes and a second H215O scan was performed, followed 10 minutes later by a second C15O scan. Patients remained in the hospital for additional observation, and were scanned using the same procedure 24 hours after the CA4P infusion.
PET Data Analysis Image visualization and region of interest (ROI) analyses were performed using Clinical Applications Programming Package software (CTI PET Systems, Knoxville, TN). The pretreatment H215O perfusion dynamic images were summed over all time frames to generate signal-averaged added images, which enabled visualization of patient anatomy with improved signal-to-noise ratio. No processing was required to improve visualization of the C15O blood volume images. The pretreatment PET images were compared with the CT scan to aid the localization of the tumor and normal tissue. ROIs were then drawn manually, and large macroscopic areas of necrosis were avoided. The boundaries were drawn conservatively within the margin of the structures to minimize the effects of spillover and patient movement. ROIs were obtained for all of the patients imaged. Because the patient positioning was maintained throughout each PET scanning session, the same ROIs were applied to the dynamic blood flow images and blood volume images obtained before and 30 minutes after CA4P administration. Because repositioning was required for the 24 hours after CA4P treatment scans, independent ROIs were drawn. For each tumor or normal tissue studied, ROIs were defined on every plane where the structure could be identified. The average measured radioactivity of all pixels within each ROI was computed, and the ROI concentrations over all planes were averaged to calculate the mean activity concentrations over the entire volume. For the dynamic blood flow images, the average radioactivity in each ROI was calculated for each time frame to generate mean ROI time-activity curves.
Blood Volume Modeling
Blood Flow Modeling
Systemic Hemodynamic Parameters
Statistical Analyses
Between November 1998 and January 2000, 34 patients were enrolled onto the phase I study (13 were enrolled at the Hammersmith Hospital). An additional patient was enrolled at Mount Vernon Hospital but was scanned at the Hammersmith Hospital. Table 1  summarizes the patient characteristics for the 14 patients enrolled for PET. No data were obtained for patient 11 because of technical problems with the administration of the radiotracers. For patients enrolled at the Hammersmith Hospital, the success rate in obtaining PET data as part of a phase I dose-escalation study was 93% for the 14 patients in whom scanning was attempted. Data were obtained at all dose levels, and this was facilitated by the intrapatient dose escalation.
Appendix 1
Table 3  summarizes the vascular parameter data obtained for ROIs in normal spleen and kidney. Perfusion was higher in normal tissue than in tumor tissue, and the blood volume was higher in spleen than in either tumor or kidney. Borderline significant CA4P-induced reductions in spleen (P = .018) and kidney (P = .026) perfusion were measured 30 minutes after CA4P administration, which returned to pretreatment levels 24 hours after treatment. Figure 5 shows parametric images of CA4P-induced changes in perfusion in the spleen, and illustrates how PET was used to visualize the rapid effects of CA4P in tissues. These images were obtained for all tissues and used to confirm visually the measured effects seen from the ROI data. Borderline significant reductions were seen in blood volume for both spleen and kidney 30 minutes after CA4P administration. Although there was some indication of dose-dependent changes in spleen perfusion (n = 9; rho = -0.51; P = .22) and blood volume (n = 10; rho = -0.48; P = .16), for the numbers analyzed the weak correlations were not statistically significant. There was no indication of dose-dependent changes in kidney perfusion (n = 20; rho = -0.03; P = .89) or blood volume (n = 19; rho = -0.25; P = .30). There also were no significant changes measured in either parameter or tissue at 24 hours versus baseline. Finally, no significant changes were measured in either parameter, time point, or normal tissue when doses 52 mg/m2 were analyzed.
The model used for estimating blood flow from the PET data also yielded an estimate of the tissue volume of distribution of water (Table 4 ). The fractional volume of distribution of water was similar in tumor and kidney and highest in spleen. CA4P reduced the volume of distribution in all of the tissues. The changes were statistically significant in the kidney (P < .0005), and had borderline statistical significance in the spleen (P = .028). The changes seen at 30 minutes in the kidney were dose dependent (rho = -0.50; P = .024). Twenty-four hours after drug administration there were no significant differences from the pretreatment data.
Table 5 summarizes the systemic hemodynamic results. There was a statistically significant reduction at 30 minutes compared with pretreatment in cardiac output and pulse rate. There were no changes in stroke volume. Blood pressure increased in response to CA4P administration, and there was a significant correlation between CA4P dose and the increase in both systolic (rho = 0.52; P = .024) and diastolic (rho = 0.70; P = .0009) blood pressure. There was no significant difference in cardiac output before CA4P administration versus 24 hours after CA4P administration.
This is the first report of the use of PET to measure vascular pharmacodynamics as part of a phase I dose-escalation study of a tumor vascular targeting agent. The enrollment requirement for a tumor suitable for PET imaging ensured a high success rate in obtaining data. The findings of the phase I study have been reported elsewhere.22 The dose-limiting toxicity was reversible ataxia at 114 mg/m2, and vasovagal syncope and motor neuropathy at 88 mg/m2. CA4P was generally well tolerated at 52 or 68 mg/m2. There are no published studies using PET to measure the antivascular effects of CA4P. However, fluorine-18–fluoro-2-deoxy-D-glucose–PET has been used to show concordance between CA4P-induced metabolic changes and histologic measurements in an experimental tumor model.27
Significant reductions in tumor perfusion were measured using PET 30 minutes after administration of CA4P. This finding in humans is consistent with data from experimental models in which rapid reductions in blood flow have been recorded for a variety of tumor types.11,28–30 Moreover, the magnitude of the reduction seen (30% to 49%) was similar to the reported values of 37%29 and 35%28 in animal tumors 1 hour after CA4P administration. The dose-dependent reductions in tumor blood flow are also consistent with the findings from animal models,28,31 as is the observation of a dose threshold effect.5 Finally, although the reduction at 24 hours compared with pretreatment remained significant, the data indicate that the effect of CA4P on tumor perfusion was reversible (Fig 2
The borderline significant or significant changes in spleen, kidney, and systemic hemodynamic parameters show that CA4P affected not only the tumor but also normal tissues. The lack of effect on stroke volume indicates that CA4P has no direct affect on the heart. However, the rapid 10% decrease in cardiac output to all tissues is likely to result from increased peripheral vascular resistance caused by CA4P (ie, the drug affects normal tissues first and then cardiac output is reduced). The 6% decrease in kidney perfusion is consistent with the 10% decrease in cardiac output to all tissues. The systemic effects observed correspond with the results from experimental models that have reported increased arterial pressure11 and decreased normal tissue perfusion11,28 after CA4P administration. The CA4P-induced reductions in spleen perfusion were higher (35%) than expected from the 10% decrease in cardiac output. The latter finding supports the results from experimental models in which larger effects have been reported for spleen than for other normal tissues,11,28 indicating that there may be tissue-specific differences in CA4P vascular response. The mechanism behind the spleen sensitivity to a vascular targeting agent needs to be investigated in future studies. The data presented in this report show that the vascular effects of CA4P are not entirely tumor specific, but the slower recovery in the tumor compared with that in normal tissue indicates some tumor specificity. Twenty-four hours after CA4P administration the spleen and kidney perfusion and blood volume had returned to pretreatment levels. In the tumor, however, significant reductions in tumor perfusion were still measurable at doses Data also were obtained for the volume of distribution of water, which reflects the amount of tissue that is exchanging water with blood during scanning.33 The values for the volume of distribution seen in tumor, spleen, and kidney were higher than the values reported for breast tissue, which has a high fat and low water content.33 Although not significant in the tumor, CA4P administration led to a reduction in the volume of distribution of water. The latter results, together with the finding of reductions in both perfusion and blood volume, support the results from experimental tumors that show a complete vascular shutdown after CA4P administration. If a vasoactive drug resulted solely in increased perfusion, no changes would be expected for blood volume or volume of distribution. Likewise, a drug that resulted solely in decreased perfusion would not alter blood volume. In contrast, a drug that caused vascular shutdown would affect all vascular parameters.
Although drug-induced changes in vascular parameters were seen, the effects did not result in any clinical tumor responses, with the possible exception of one patient given 68 mg/m2 who had an improvement in adrenocortical carcinoma liver metastases.22 The insights into the mechanism of action of CA4P provided by this study, however, should be useful for the design of future clinical trials, particularly with regard to the optimization of therapeutic gain. The threshold effect seen at doses In summary, the results reported here show that CA4P causes rapid changes in human tumor perfusion and blood volume consistent with the vascular shutdown mechanism of action indicated from experimental tumor models. CA4P was also shown to induce rapid changes in normal tissue and systemic vascular parameters. The CA4P effects on tumor, spleen, kidney, and systemic vascular parameters were reversible, with some indication that the changes in tumor were reversed more slowly than in the normal tissues studied. The conclusion from this report is that CA4P induced rapid changes in tumor, normal tissue, and systemic vascular parameters that were measurable using PET.
We thank Ric Swindell, Department of Medical Statistics, Christie Hospital NHS Trust, Manchester, United Kingdom, for the statistical analyses.
Supported by Cancer Research United Kingdom (program grants C153/A1797 and C153/A1802) and OXiGENE, Inc, Watertown, MA.
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