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Originally published as JCO Early Release 10.1200/JCO.2005.04.143 on July 18 2005 © 2005 American Society of Clinical Oncology. Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Pharmacodynamic Measure of Response After Acute Dosing of AG-013736, an Oral Angiogenesis Inhibitor, in Patients With Advanced Solid Tumors: Results From a Phase I StudyFrom the University of Wisconsin Comprehensive Cancer Center, Madison, WI; University of California, San Francisco Comprehensive Cancer Center, San Francisco, CA; The University of Texas M.D. Anderson Cancer Center, Houston, TX; Pfizer Global Research and Development, La Jolla, CA, Groton, CT, and Ann Arbor, MI; and VirtualScopics LLC, Rochester, NY Address reprint requests to Roy S. Herbst, MD, PhD, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 432, Houston, TX 77030; e-mail: rherbst{at}mdanderson.org
PURPOSE: Identifying suitable markers of biologic activity is important when assessing novel compounds such as angiogenesis inhibitors to optimize the dose and schedule of therapy. Here we present the pharmacodynamic response to acute dosing of AG-013736 measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). PATIENTS AND METHODS: Thirty-six patients with advanced solid tumors were treated with various doses of AG-013736. In addition to standard measures of objective disease response and pharmacokinetic analysis, DCE-MRI scans were acquired at baseline and repeated at cycle 1—day 2 after the scheduled morning dose of the AG-013736 in 26 patients. Indicators of a vascular response, such as the volume transfer constant (Ktrans) and initial area under the curve (IAUC), were calculated to assess the effect of treatment on tumor vascular function.
RESULTS: Evaluable vascular response data were obtained in 17 (65%) of 26 patients. A linear correlation was found in which the percentage change from baseline to day 2 in Ktrans and IAUC was inversely proportional to AG-013736 exposure. Using a conservative a priori assumption that a CONCLUSION: A sufficient decrease in tumor vascular parameters was observed at a dose chosen for additional phase II testing by conventional toxicity criteria. In addition, the day 2 vascular response measured using DCE-MRI seems to be a useful indicator of drug pharmacology, and additional research is needed to determine if it is a suitable marker for predicting clinical activity.
AG-013736 is a substituted indazole derivative discovered by using a structure-based drug design. Mechanistically, AG-013736 inhibits the tyrosine kinase activities of all known vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor receptor-ß, and c-Kit in low nanomolar concentrations. AG-013736 selectively blocks VEGF-stimulated receptor autophosphorylation at subnanomolar concentrations and therefore inhibits endothelial cell proliferation and survival. In mice, AG-013736 inhibited tumor vascular angiogenesis and the growth of many human xenografts, as well as murine lung tumors. Furthermore, AG-013736 significantly inhibited the development and progression of metastasis to the lung and the lymph nodes in an orthotopically transplanted human melanoma tumor model.1 Given the strong preclinical evidence for antiangiogenic, antitumor, and antimetastatic activity, a first-in-human phase I trial was conducted using AG-013736 in patients with advanced solid malignancies. The development of novel therapeutic agents targeting angiogenesis is challenging without a validated biomarker2 of an antiangiogenic effect in humans. Measuring the efficacy of this type of targeted agent is difficult given that it can be slower in onset, often cytostatic, and thus not easily evaluable by standard objective response criteria.3 Having a suitable biomarker may therefore allow improved patient selection and increase the probability of detecting a true antitumor effect, as well as predict clinical activity after only a short course of treatment.4 In addition, the biologically active dose may be much lower than the traditional maximum tolerated dose (MTD) such that chronic use at the MTD might result in an altered therapeutic index.5 Biomarkers for antiangiogenic activity assessed in initial trials (ie, endostatin) have included serum VEGF levels, dynamic computed tomography, ultrasound, and positron emission tomography scans.6,7 Although these end points were evaluable, no consistent response to endostatin has been reported. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been used as a method to evaluate the microenvironment occurring within tumors.8,9 Factors such as blood flow, microvessel permeability, vessel size, tissue oxygenation, and metabolism can be characterized with MRI techniques.10 DCE-MRI has already been shown to be able to monitor and predict the effects of treatments such as neoadjuvant chemotherapy in breast,11 bladder,12 and bone cancer,13 radiation therapy in rectal14 and cervical cancer,15 and possibly androgen-ablative treatment in prostate cancer.16 More recently, its use in assessing acute effects in tumor vascular parameters has been evaluated after treatment with angiogenesis inhibitors. For example, preclinical testing using DCE-MRI in a prostate cancer xenograft model after treatment with a VEGF receptor-2 tyrosine kinase inhibitor showed decreases in the volume transfer constant (Ktrans) consistent with a reduction in tumor vascular permeability and perfusion.17 The antibody against VEGF-A, bevacizumab, produced similar decreases in xenografts.18 Preclinical xenograft studies using DCE-MRI were subsequently conducted that demonstrated that AG-013736 produced rapid and marked decreases in vascular permeability in BT474 xenografts.19 It was hypothesized, therefore, that DCE-MRI would be a suitable biomarker for study with AG-013736 in the clinic.
At the time this trial was initiated, the utility of DCE-MRI had already been explored in several phase I trials, including those for PTK787/ZK 222584,20 combretastatin A4 phosphate,21 ZD6126,22 and 5,6-dimethylxanthenone-4-acetic acid.23 In the trial by Morgan et al,20 rapid reduction of enhancement of tumors secondary to presumed reduction in both tumor vessel permeability and vascularity was seen on DCE-MRI after treatment with PTK787/ZK 222584. As reported, a decrease of
Patient Selection Patients were enrolled at the University of Wisconsin Comprehensive Cancer Center (Madison, WI), The University of Texas M.D. Anderson Cancer Center (Houston, TX), and University of California, San Francisco Comprehensive Cancer Center (San Francisco, CA) between May 2002 and January 2004. All patients were  18 years of age with histologically confirmed advanced nonhematologic cancer refractory to standard therapy or for which no effective therapy was available. An Eastern Cooperative Group performance status of  2 and a life expectancy of 12 weeks were required. All patients must have recovered from toxicities of prior treatment, as well as not received any radiotherapy, investigational therapy, or chemotherapy within 4 weeks of study entry (6 weeks for carboplatin and nitrosoureas, 2 weeks for antibodies or immunotherapy). All patients had adequate bone marrow function (as defined by an absolute neutrophil count 1,500/µL, platelet count 75,000/µL, and hemoglobin count 10 g/dL), renal function (serum creatinine 1.5 mg/dL), and liver function (bilirubin 1.5 mg/dL, transaminases 2.5x upper limit of normal or 5x upper limit of normal with documented liver metastasis) at baseline. No prior history of occlusive coronary artery disease, clinically significant gastrointestinal abnormalities (including inability to take oral medications, malabsorption syndrome, prior gastric resection, active gastrointestinal bleeding, or ulcerative disease), or uncontrolled brain metastasis was permitted. In addition, current or required use of potent cytochrome P450 agents (CYP3A4 inhibitors or CYP3A4/CYP1A2 inducers), chronic use of H2 antagonists or proton-pump antacids, and requirement for anticoagulant therapy (except for low-dose therapy to maintain patency of central venous access devices) was not allowed. By amendment, proteinuria 500 mg/24 hours, squamous cell lung cancer, centrally located lung lesions (of any histology), and uncontrolled hypertension (systolic > 140 mmHg, diastolic > 90 mmHg) were excluded because of observed toxicities in this and similar trials. After the MTD was defined, only patients able to comply with separate criteria to further characterize functional imaging with tumor lesions readily amenable to DCE-MRI scanning were enrolled.
Drug Administration and Study Design AG-013736 was supplied as 1- and 10-mg film-coated tablets. The 10-mg tablet contained a bisect to allow manual splitting of the tablet to achieve a 5-mg dose. AG-013736 was administered daily (either once or twice daily), with no scheduled breaks. Each cycle of therapy was defined as 28 days.
Tumor Assessments
PK Assessment Standard plasma PK parameters including maximum plasma concentration (Cmax), elimination half-life (t1/2), and area under the curve (AUC)0-12 and AUC0-24 for AG-013736 after single and multiple doses were estimated by using noncompartmental methods. The main effect of dose on AG-013736 PK parameters was evaluated by analysis of variance (ANOVA). Accumulation of AG-013736 with multiple dosing was evaluated by using two-way ANOVA.
DCE-MRI Methodology For the dynamic contrast technique, a three-dimensional (3D) fast-spoiled gradient-recalled echo sequence was used to acquire T1-weighted images before, during, and after intravenous administration of 0.1 mmol/kg gadopentetate dimeglumine infused with a magnetic resonance-compatible injector at 3 mL/sec and followed by a 20-mL saline flush at 3 mL/sec. All 3D DCE-MRI data were acquired by using GE 1.5-T EchoSpeed scanners (256 x 128 matrix; ten 5-mm slices acquired every 11.04 seconds for 5.53 minutes; 22- to 36-cm axial field of view). Acquired images were sent from each site to a central image-analysis vendor (VirtualScopics, LLC, Rochester, NY) for quality assessment and final analysis. For the occasional cases in which the entire volume of the tumor was not included in the transverse field of view, only anatomically corresponding slices between baseline and day 2 were analyzed. Using the VirtualScopics Perfusion Module (version 1.0), tumor margins were identified in this study by using a semiautomated image-analysis technique (geometrically constrained region growth24), and blood regions were manually identified in the center of large vessels with no apparent flow artifact. Signal-intensity time curves were generated by averaging all voxels in each region of interest at each time point. Curves were normalized by subtracting the average precontrast signal intensity for each region of interest. Because signal intensity varies nearly linearly with tracer concentration, using the pulse sequences and concentrations expected in this study, it was determined that conversion to tracer concentration via T1 mapping would increase rather than decrease measurement variability. Both blood and tumor data were fit to gamma-variate curves to reduce noise. These data were fit to the Tofts model to determine the Ktrans value25 and IAUC (ie, first 90 seconds)26 in the tumor divided by the blood IAUC (to account for differences in the blood input function between studies). Parameters (Ktrans and IAUC) were averaged across all voxels included in the tumor covered by the 3D field of view (limited to 5 cm in the transaxial plane).
Correlation of Pharmacodynamic to PK Data
Patient Characteristics A total of 36 patients with advanced solid malignancies were treated by using AG-013736 as part of this phase I trial. The median age was 57 (range, 41 to 76) years. There were 16 men and 20 women. The cancers treated included 13 breast, 5 thyroid, 6 renal cell, 5 non–small-cell lung, two squamous cell skin, and one patient each with ocular melanoma, Merkel cell, adenoid cystic, prostate, and colorectal carcinoma. All patients had metastatic disease, and 26 (72%) had received prior chemotherapy (please refer to the accompanying AG-013736 clinical article27 for more details regarding patient characteristics, toxicities, and PK). The dose levels tested in each cohort are listed in Table 1. As a result of dose-limiting toxicities, dose de-escalation was performed with the eventual MTD being defined as 5 mg by mouth given twice daily in the fasted state. Cohort six was added to evaluate the effects of antacids on AG-013736 absorption and obtain additional DCE-MRI data at the lower boundary of the exposure-response curve.
Toxicities The primary dose-limiting toxicity observed for AG-013736 was hypertension. Other dose-limiting toxicities included stomatitis, diarrhea, and elevation of liver transaminases. At the dose recommended for phase II studies (5 mg twice daily), no unmanageable or irreversible adverse events were encountered.
PK
DCE-MRI Results A total of 26 patients in cohorts two to six were assessed by using DCE-MRI at baseline, day 2 (at the estimated Cmax after ingestion of the morning AG-013736 dose), and, when possible, weeks 4 and 8 after treatment. Of these patients, 17 (65%) had DCE-MRI data from baseline and day 2 scans that could be interpreted reliably. Reasons for inadequate DCE-MRI image-data quality included inability to detect an adequate blood contrast input function (n = 4), severe motion during the dynamic scan acquisition that could not be corrected with available postacquisition motion-correction techniques (n = 3), insufficient target-lesion size (n = 1), and/or missing data on day 2 (n = 1). A rapid decrease in tumor vascular parameters, as measured by mean Ktrans and IAUC, could be seen on day 2 after AG-013736 administration. This is visibly demonstrated in Figure 1, which represents a patient with adenoid cystic carcinoma who had a reduction in tumor vascular parameters and tumor mass meeting criteria for a partial response. A > 50% decrease in Ktrans and IAUC was demonstrated by day 2 of therapy, which persisted through week 4 of treatment. Although the average Ktrans and IAUC measurements increased at week 8, the regions of nonperfused tumor necrosis had disappeared, and the residual tumor IAUC values remained low. Figure 2 illustrates spatial changes in IAUC within a representative single-slice image of a lung metastasis in a patient with metastatic renal cell carcinoma. Additional patients were observed to have marked changes in their tumor vascular parameters between baseline and day 2. Table 2 shows a summary of the tumor characteristics and change in vascular parameters in all patients who successfully completed DCE-MRI assessments.
Correlation Between DCE-MRI Results and AG-013736 PK Statistically significant decreases were noted for both percent change in mean Ktrans and IAUC for increasing values of log-transformed AUC and Cmax, respectively. Figure 3 shows percent change in the tumor mean Ktrans plotted against plasma AG-013736 AUC0-24. It is evident that higher exposures of AG-013736 were associated with a greater decrease in mean Ktrans, with hints of a plateau effect as suggested by data from a few patients with AUCs exceeding 500 ng · h/mL. A similar correlation was seen with mean IAUC with respect to plasma AG-013736 AUC0-24 concentrations (Fig 4). Likewise, the percent change in mean Ktrans or IAUC plotted against the peak plasma AG-013736 levels (Cmax) showed similar correlations (data not shown).
Objective Tumor Response Durable partial responses were seen in two patients with renal cell cancer and one patient with adenoid cystic carcinoma in this phase I trial.
Angiogenesis inhibition remains a promising approach for new drug development in cancer therapy. In fact, blocking VEGF has already been shown to have potent antivascular effects28 and significant clinical activity as evidenced by an improvement in overall survival when combined with standard chemotherapy in colorectal cancer.29 The difficulty with developing angiogenesis inhibitors is that standard objective response criteria (tumor shrinkage) may not always be adequate. Because many of these compounds are cytostatic and may simply delay disease progression, identification of biologic markers indicative of a tumor vascular response is necessary to help better define the optimal dose and schedule of these agents. We found AG-013736 to be well tolerated at the dose of 5 mg, twice daily, administered orally on a continuous basis. In addition, AG-013736 was shown to cause significant decreases in DCE-MRI vascular parameters by day 2 of treatment when assessed at the anticipated Cmax (after the scheduled morning dose of AG-013736). This decrease seemed dose dependent, because increased drug exposures did seem to correlate with a decrease in mean Ktrans and IAUC. The unanswered question that remains is what decrease in Ktrans or IAUC would be considered clinically significant or predictive of response to AG-013736?
Although the minimum change in Ktrans and IAUC necessary to be labeled "clinically significant" remains uncertain, Gailbraith et al30 reported that, for an individual patient, a decrease in median Ktrans of a single representative tumor image slice by > 45% was needed to be 95% confident that the decrease was a result of treatment effect rather than spontaneous changes or measurement error. For this study, we arbitrarily chose a priori to define an objective tumor vascular response as any decrease in mean Ktrans
The use of DCE-MRI to evaluate changes in vascular parameters or biologic effect after treatment with an angiogenesis inhibitor is still considered exploratory. As a result, the purpose of performing dynamic imaging during phase I studies can be summarized as follows: (1) to confirm the mechanistic action of the drug, (2) to assist in selection of phase II dosing regimen(s), (3) to aid in drug scheduling, and (4) to help enrich subpopulations in future trials to improve response.33
Did Imaging Support the Mechanistic Goals of the Drug?
Did Imaging Assist in the Drug Scheduling for Additional Trials?
Can Imaging Assist Enriching Subpopulations for Future Trials? In summary, AG-013736 has shown promising antitumor activity in patients with advanced solid malignancies as evidenced by durable partial responses in renal cell and adenoid cystic carcinomas. The recommended phase II dose of AG-013736 was determined to be 5 mg, twice daily, administered orally in the fasted state on a continuous basis. This dosing resulted in a mean plasma AG-013736 AUC of 460 ng · h/mL, which is well within the range of pharmacodynamic activity as determined by the DCE-MRI. Even with the somewhat high intersubject variability (90% coefficient of variation) associated with this AUC, the majority of patients at the recommended phase II dose exceeded the exposure associated with vascular response as determined by DCE-MRI. The measured changes in tumor vascular parameters were present by day 2 of treatment, with greater decreases in mean Ktrans and IAUC seen with increasing plasma concentrations of AG-013736. Because suggestions of a plateau effect were seen with regard to tumor vascular effects of AG-013736, the plasma exposures associated with a biologically active dose were close to the exposures associated with the MTD. This study provides additional support for using DCE-MRI as a pharmacologic biomarker of antiangiogenic activity. Rapid decreases in Ktrans after AG-013736 therapy support the contention that this small molecule inhibitor achieves concentrations sufficient to antagonize VEGF receptor signaling in human malignancies. Furthermore, preclinical DCE-MRI results seem to have translated in the clinical setting, bolstering confidence in the use of DCE-MRI as a clinical biomarker of VEGF receptor tyrosine kinase inhibition. Although the clinical relevance of acute changes in vascular parameters remains uncertain, it is clear that a lack of decrease in mean Ktrans or IAUC was associated with a lack of a clinically meaningful response to continual therapy with AG-013736 in this trial. In conclusion, the assessment of tumor vascular parameters using DCE-MRI is possible in a multi-institutional setting and can provide useful information regarding dose and schedule selection for novel agents. Although additional testing is still necessary, it seems that tumor vascular parameters as measured by DCE-MRI scans may be a useful surrogate marker in predicting clinically meaningful response to therapy for this new class of agents. We currently are evaluating DCE-MRI further in a phase II study using AG-013736 in non–small-cell lung cancer. Incorporation of dynamic imaging should be considered in all early trials targeting tumor angiogenesis.
Although all authors have completed the disclosure declaration, the following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) $10,000 (B) $10,000-99,999 (C) a $100,000 (N/R) Not Required
We are thankful to Dona Alberti, Kimberly Binger, Cathy Henceroth, Tracey Borst, Marina Kenzer, Kavitha Krishnan, Michelle Purdom, Debra Chicks, and Krista McAlee for their help in patient recruitment, data management, and patient care during the conduct of this phase I trial. We also thank David Shalinsky, PhD, Dana Hu-Lowe, PhD, and Paul Bycott, PhD, for helpful discussions aimed at setting the clinical criteria for using DCE-MRI in this study.
Supported by research support provided by Pfizer Global Research and Development, San Diego, CA, and Groton, CT. Presented at the American Association for Cancer Research-National Cancer Institute-European Organisation for Research and Treatment of Cancer International Conference on Molecular Targets and Cancer Therapeutics, November 17-21, 2003, Boston, MA; 6th International Symposium on Antiangiogenesis Agents, January 30-February 1, 2004, San Diego, CA; American Society of Clinical Oncology Annual Meeting, June 5-8, 2004, New Orleans, LA; and International Society of Magnetic Resonance in Medicine, May 15-21, 2004, Kyoto, Japan. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Pfizer Global Research and Development: AG-013736: Investigator's Brochure. Pfizer Global Research and Development, La Jolla, CA, 2004 2. DeGruttola VG, Clax P, DeMEts DL, et al: Considerations in the evaluation of surrogate endpoints in clinical trials: Summary of a National Institutes of Health Workshop. Controlled Clin Trials 22:485-502, 2001[CrossRef][Medline]
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6. Thomas JP, Arzoomanian RZ, Alberti D, et al: Phase I pharmacokinetic and pharmacodynamic study of recombinant human endostatin in patients with advanced solid tumors. J Clin Oncol 21:223-231, 2003
7. Herbst RS, Mullani NA, Davis DW, et al: Development of biologic markers of response and assessment of antiangiogenic activity in a clinical trial of human recombinant endostatin. J Clin Oncol 20:3804-3814, 2002 8. Yuh WT: An exciting and challenging role for advanced contrast MR imaging. J Magn Reson Imaging 10:221-222, 1999[CrossRef][Medline] 9. Taylor JS, Tofts PS, Port R, et al: MR imaging of tumors microcirculation: Promise for a new millennium. J Magn Reson Imaging 10:260-266, 1999[CrossRef][Medline] 10. Padhani AR: Dynamic contrast-enhanced MRI in clinical oncology: Current status and future directions. J Magn Reson Imaging 16:407-422, 2002[CrossRef][Medline] 11. Knopp MV, Brix G, Junkermann HJ, et al: MR mammography with pharmacokinetic mapping for monitoring of breast cancer treatment during neoadjuvant chemotherapy. Magn Reson Imaging Clin N Am 2:633-658, 1994[Medline]
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16. Padhani AR, MacVicar AD, Gapskinski CJ, et al: Effects of androgen deprivation on prostatatic morphology and vascular permeability evaluated with MR imaging. Radiology 218:365-374, 2001 17. Checkley D, Tessier JJ, Kendrew J, et al: Use of dynamic contrast-enhanced MRI to evaluate acute treatment with ZD6474, a VEGF signaling inhibitor, in PC-3 prostate tumors. Br J Cancer 89:1889-1895, 2003[CrossRef][Medline] 18. Brasch R, Pham C, Shames D, et al: Assessing tumor angiogenesis using macromolecular MR imaging contrast media. J Magn Reson Imaging 7:68-74, 1997[Medline] 19. Wilmes LJ, Hylton N, Wang DH, et al: AG-013736, a novel VEGFR TK inhibitor, suppresses tumor growth and vascular permeability in human BT474 breast cancer xenografts in nude mice. Proc Am Assoc Cancer Res 44:863, 2003 (abstr 3772)
20. Morgan B, Thomas AL, Drevs J, et al: Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastasis: Results from two phase I trials. J Clin Oncol 21:3955-3964, 2003
21. Stevenson JP, Rosen M, Sun W, et al: Phase I trial of the antivascular agent combretastatin A4 phosphate on a 5-day schedule to patients with cancer: Magnetic resonance imaging evidence for altered blood flow. J Clin Oncol 21:4428-4438, 2003
22. Evelhoch JL, LoRusso PM, He Z, et al: Magnetic resonance imaging measurements of the response of murine and human tumors to the vascular-targeting agent ZD6126. Clin Cancer Res 10:3650-3657, 2004
23. Galbraith SM, Rustin G, Lodge MA, et al: Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging. J Clin Oncol 20:3826-3840, 2002 24. Ashton EA, Takahashi C, Berg MJ, et al: Accuracy and reproducibility of manual and semiautomated quantification of MS lesions by MRI. J Magn Reson Imaging 17:300-308, 2003[CrossRef][Medline] 25. Tofts PS, Brix G, Buckley DL, et al: Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: Standardized quantities and symbols. J Magn Reson Imaging 10:223-232, 1999[CrossRef][Medline] 26. Mattiello J, Evelhoch JL: Relative volume-average murine tumor blood flow measurement via deuterium nuclear magnetic resonance spectroscopy. Magn Reson Med 18:320-334, 1991[Medline] 27. Rugo HS, Herbst RS, Liu G, et al: Phase I Trial of the Oral Antiangiogenesis Agent AG-013736 in Patients With Advanced Solid Tumors: Pharmacokinetic and Clinical Results. J Clin Oncol 23:10.1200/JCO.2005.04.192 28. Willett CG, Boucher Y, di Tomasso E, et al: Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145-147, 2004[CrossRef][Medline] 29. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 30. Galbraith SM, Lodge MA, Taylor NJ, et al: Reproducibility of dynamic contrast-enhanced MRI in human muscle and tumours: Comparison of quantitative and semi-quantitative analysis. NMR Biomed 15:132-142, 2002[CrossRef][Medline] 31. Padhani AR, Husband JE: Dynamic contrast-enhanced MRI studies in oncology with an emphasis on quantification, validation and human studies. Clin Radiol 56:607-620, 2001[CrossRef][Medline] 32. Rijpkema M, Kaanders J, Joosten F, et al: Method for qualitative mapping of dynamic MRI contrast agent uptake in human tumors. J Magn Reson Imaging 14:457-463, 2001[CrossRef][Medline]
33. Collins JM: Functional imaging in phase I studies: Decorations or decision making? J Clin Oncol 21:2807-2809, 2003 Submitted November 9, 2004; accepted March 24, 2005. Related Editorial
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ABSTRACT
INTRODUCTION
