Detection of Early Tumor Response to Axitinib in Advanced Hepatocellular Carcinoma By

11 Detection of Early Tumor Response to Axitinib in Advanced Hepatocellular2 Carcinoma by Dynamic Contrast Enhanced Ultrasound 1,2 1 1 1 3 Glen M. Lo , MD, Hassan Al Zahrani , MD, Hyun-Jung Jang , MD, Ravi Menezes , PhD, 3 3 4, 5 1 4 John Hudson , PhD, Peter Burns , PhD, Mairéad G McNamara , MB PhD, Sonja Kandel , 1 4 1 1 5 MD, Korosh Khalili , MD, Jennifer Knox , MD, Patrik Rogalla , MD, Tae Kyoung Kim , MD67 Affiliations8 1. Medical Imaging, University of Toronto, Toronto, ON, Canada. 9 2. Department of Radiology, Sir Charles Gairdner Hospital, QEII Medical Centre, Perth, 10 Western Australia.11 3. Department of Medical Biophysics, Sunnybrook Health Sciences Centre, Toronto, ON, 12 Canada. 13 4. Division of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, 14 Toronto, ON, Canada.15 5. Department of Medical Oncology, The Christie NHS Foundation Trust/University of 16 Manchester (Institute of Cancer Sciences), Manchester, United Kingdom.1718 Corresponding author:19 Tae Kyoung Kim, MD20 Joint Department of Medical Imaging, University Health Network21 Toronto General Hospital Peter Munk Building, 1 PMB-2981 2 22 585 University Avenue Toronto, Ontario M5G 2N223 Phone: 1-416- 340-337224 Fax: 1-416-593-050225 [email protected] 2 326 ABSTRACT2728 This study aimed to evaluate the utility of dynamic contrast-enhanced ultrasound (DCE-US) in29 measuring early tumor response of advanced hepatocellular carcinoma (HCC) to axitinib.30 Twenty patients were enrolled (age 18–78 years; median 65). DCE-US was performed with31 bolus injection and infusion/disruption-replenishment. Median overall survival (OS) was 7.132 months (1.8-27.3) and progression free survival (PFS) was 3.6 months (1.8-17.4). Fifteen33 patients completed infusion scans and 12 completed bolus scans at 2 weeks. Among the34 perfusion parameters, fractional blood volume at infusion (INFBV) decreased at 2 weeks in 10/1535 (16–81% of baseline, mean 47%) and increased in 5/15 (116–535%, mean 220%). This was not36 significantly associated with PFS (p=0.310) or progression at 16 weeks (p=0.849) but was37 borderline statistically significant (p=0.050) with OS, limited by a small sample size. DCE-US38 is potentially useful in measuring early tumor response of advanced HCC to axitinib, but a39 larger trial is needed.4041 ABSTRACT WORD COUNT: 1504243 KEYWORDS: dynamic contrast-enhanced ultrasound, hepatocellular carcinoma, liver 44 neoplasms, axitinib, tumor response, perfusion3 4 45 INTRODUCTION4647 Novel therapeutics for the treatment of hypervascular tumors, such as hepatocellular carcinoma48 (HCC), target tumor neoangiogenesis creating the potential for developing imaging techniques49 that can assess early treatment response by measuring early changes in tumor perfusion, rather50 than assess the later change in tumor size (Eisenhauer et al. 2009; Jain et al. 2009; O'Connor et51 al. 2008; Turkbey et al. 2009).5253 HCC is a hypervascular neoplasm, with tumor vascularity lending itself to imaging of perfusion.54 Perfusion imaging can be performed using several modalities (e.g. CT, MRI, US, PET), with55 ultrasound being relatively accessible, cheaper and not involving ionizing radiation (Provenzale56 2007). Several groups have published promising results of dynamic contrast-enhanced57 ultrasound (DCE-US) monitoring in various tumors measuring response to antiangiogenics,58 including renal cell carcinoma (Lamuraglia et al. 2006; Williams et al. 2011), advanced HCC59 (Assunta et al. 2013; Frampas et al. 2013; Sugimoto et al. 2013) and gastrointestinal stromal60 tumors (GIST) (Knieling et al. 2013). DCE-US is now endorsed to monitor treatment response61 in GIST by the European Society of Medical Oncology (ESMO / European Sarcoma Network62 Working Group 2012).6364 DCE-US has been reported useful in early monitoring of response to sorafenib (an established65 tyrosine kinase inhibitor) in advanced HCC, (Assunta et al. 2013; Knieling et al. 2012;66 Shiozawa et al. 2012; Sugimoto et al. 2013). Axitinib is a novel selective tyrosine kinase67 inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFs) 1, 2, and 3 (Choueiri68 2008) and has been investigated as a second-line treatment option in advanced HCC when first-69 line therapy with sorafenib failed. This study is a sub-study of a phase II trial of second-line 4 570 axitinib following prior antiangiogenic therapy in advanced HCC (McNamara et al. 2015),71 focusing on the utility of DCE-US as an imaging biomarker. The results reported by McNamara72 et al and from a randomized phase II study of axitinib versus placebo plus best supportive care73 in second-line treatment of advanced HCC (Kang et al. 2015) concluded that further study of74 this agent should be in a selected population incorporating potential biomarkers of response. To75 our knowledge, there has been no report on the use of DCE-US as an imaging biomarker for76 axitinib treatment monitoring in HCC.7778 In addition, antiangiogenic therapy not only changes the perfusion of liver tumors, but also has79 an effect on the perfusion of the liver parenchyma. Perfusion change of liver parenchyma with80 the use of antiangiogenics has been recently reported to predict major adverse events as a result81 of sorafenib therapy (Sugimoto et al. 2013).8283 The purpose of this study was to determine if DCE-US was useful in the early detection of84 tumor response to axitinib in the treatment of patients with advanced HCC and to determine if85 DCE-US can detect perfusion changes of liver parenchyma related to the use of axitinib.8687 MATERIALS AND METHODS8889 This is a sub-study of a prospective single arm, open-label phase II trial of axitinib in advanced90 HCC (McNamara et al. 2015). The institutional Research Ethics Board approved the trial.91 Written informed consent was obtained from all patients.9293 Subjects5 6 9495 The clinical trial enrolled 30 patients with advanced HCC for treatment with axitinib96 (McNamara et al. 2015). Eligible patients had unresectable and/or metastatic HCC and were97 Child-Pugh score of A or B7, with measurable progressive disease after prior treatment with98 antiangiogenics. Twenty patients consented to undergo the DCE-US sub-study and were99 prospectively enrolled from January 2011 to October 2013. Four patients were excluded100 because of incomplete imaging (their clinical condition precluded them from attending all101 imaging appointments; those that attended imaging tolerated imaging procedures). One patient102 was excluded because he did not take the trial medication although he underwent all scheduled103 DCE-US tests. Axitinib was started at 5 mg bid orally, titrated to 2-10 mg bid as tolerated (28104 days = 1 cycle). Treatment continued until progressive disease or intolerable toxicity/patient105 withdrawal. Tumor response was evaluated by multi-phasic contrast-enhanced CT, performed106 at baseline and every 8 weeks as per protocol (McNamara et al. 2015).107108 Ultrasound Scanning109110 DCE-US was performed at baseline and 2 weeks after starting axitinib. Patients were scanned111 using a Philips iU22 scanner (Philips Ultrasound, Bothell, WA) with a C5-1 probe, in dual-112 imaging mode (contrast/grayscale), at low mechanical index (MI < 0.06) with non-linear113 imaging (power modulated pulse inversion [PMPI] mode). Patients were scanned according to114 trial protocol by one of three trial radiologists (HJ, KK, TK), experienced in DCE-US. A single115 target lesion, which was most easily accessible with ultrasound, in each patient was examined in116 either sagittal or coronal planes, so that respiratory motion was confined to the scan plane and117 could be corrected for post-processing. Tumor sizes were measured, in three planes. DCE-US118 was performed by using two different methods: bolus-injection and infusion with 6 7119 disruption/replenishment. First, a single bolus injection was measured, imaging the tumor at its120 largest visible plane. Then six disruption-replenishment acquisitions with continuous infusion of121 the contrast agent were performed at the same location. The ultrasound contrast agent used122 consisted of perflutren lipid microspheres (Definity; Lantheus, North Billerica, MA). For the123 bolus injection, 0.2 mL of contrast agent was injected into an antecubital intravenous catheter,124 followed by a 5 mL saline flush. Scanning time started at the end of the flush and was125 continuous for 2 minutes, without a breath-hold. Infusion began after the bolus technique. An126 infusion of 0.9 mL of perflutren lipid microspheres diluted in 54 mL of saline was administered127 over 12 minutes by using an injection pump (Medfusion 3500; Smiths Medical, Dublin Ohio).128 After waiting 2 minutes for the infusion to reach steady state, six disruptions (high-mechanical129 index 8-frame flash) were performed, and each corresponding replenishment sequence was130 measured over 30 seconds, with breath-hold (Williams et al. 2011). 131132 Image Analysis133134 Ultrasound data were transferred from the scanner via DVD to a separate workstation for135 analysis. Raw data was saved, to allow linearization. If the clip from either bolus or infusion136 measurements demonstrated severe respiratory motion which makes it difficult to place the137 regions of interest (ROI), a motion correction region-of-interest was drawn on the image,138 encompassing as much tumor and liver visible, and the software’s motion compensation139 algorithm applied (Williams et al. 2011). Regions of interest (ROI) were drawn: the first within140 the tumor (T) and the second in adjacent liver parenchyma (L). For tumor, a free-hand ROI was141 drawn on grayscale image as close to the tumor margin as possible, to ensure inclusion of142 peripheral tumor vascularity (Figures 1, 2). For the liver, a free-hand ROI was drawn at the7 8 143 same depth and size as the tumor ROI. Not all sonographic windows enabled adequate144 visibility of adjacent liver for a liver ROI analysis. 145146 Contrast Enhancement Models147148 Our study implemented two different methods of DCE-US with their correspondingly149 appropriate perfusion models (below). The first method relies on a single bolus of contrast150 injected intravenously in a peripheral vein. The strengths of this technique include its151 widespread use among DCE-US centers permitting a more direct comparison of results, and its152 high signal to noise ratio. In a practical setting, the method is limited to a single measurement153 per study. Reproducibility is also affected by the unknown influence of cardio-pulmonary on154 the local arterial/portal input function. Implementing the infusion method requires additional155 equipment (infusion pump), but permits multiple measurements to made in quick succession156 and has direct control over the arterial/portal input function (Hudson et al. 2015). For each157 DCE-US study, in the single bolus injection clip and six infusion clips, the observed perfusion158 in the selected region-of-interest was plotted as a time-intensity curve by the computer software159 fitting data to an appropriate model (Hudson et al. 2011), allowing for quantitative160 measurements of perfusion parameters as follows. 161162 Bolus measurements were fitted to a model using a local-density random-walk equation (Figure163 1). For the bolus injection, seven perfusion parameters were recorded:164 1. Total area under the curve (BOLAUC).165 2. Peak signal intensity (BOLPEAK).166 3. Time to peak signal intensity (BOLTTP).8 9167 4. Area under the curve wash-in (area up to peak, BOLAUC-in).168 5. Area under the curve wash-out (area after peak, BOLAUC-out).169 6. Mean transit time (BOLMTT).170 7. Inflow slope (BOLSLOPE).171172 Infusion disruption-replenishment measurements were fitted to a lognormal perfusion model,173 using in-house software (Matlab; The Mathworks Inc., Natick, MA). The resulting curve’s174 plateau reflects tumor fractional blood volume (INFBV) and its slope reflects tumor mean flow175 velocity (INFVM) (Hudson et al. 2011). The average of six (or more) measurements was used.176 For infusion or disruption/replenishment technique, two perfusion parameters were recorded: 177 1. Peak178 intensity, which reflects fractional blood volume (INFBV).179 2. Slope, which reflects flow velocity (INFVM).180181 Standard Endpoints182183 Tumor response evaluation was performed according to RECIST 1.1 at CT scan (Eisenhauer et184 al. 2009). The primary endpoint of tumor control rate in the clinical study was assessed by CT185 scan at 16 weeks by RECIST 1.1 criteria (Edeline et al. 2012). Secondary clinical endpoints186 included progression free survival (PFS) and overall survival (OS). Perfusion parameters for187 each patient were examined as a percentage change observed at the 2 week DCE-US scan,188 compared to baseline. Patients were then grouped for each perfusion parameter according to189 whether an increase or decrease in perfusion was observed.1909 10 191 Perfusion parameters were analyzed for associations with response (responders demonstrating192 stable disease or treatment response, and non-responders having progressive disease on the 16193 week CT), OS and PFS. For each parameter, patients were grouped as having increased or194 decreased perfusion and correlated with response, PFS or OS using Kaplan-Meier analysis.195 Differences between perfusion parameter subgroups (increased or decreased perfusion) were196 examined using the log-rank test. Analysis was made for associations between infusion197 parameters at the initial 2-week US scan and LFTs at 16 weeks, using Spearman’s rho198 correlation coefficients and the Mann-Whitney test.199200 RESULTS201 Fifteen patients were included in final analysis (10 men and 5 women, mean age 57 years, range202 18 to 78 years). Causes of hepatic cirrhosis included alcohol (n = 2), hepatitis B (n = 6),203 hepatitis C (n = 3) and other (n = 4). (Table. 1.)204 205 Among the 15 patients, all had complete infusion data but only 12 had complete bolus-injection206 data at 2 weeks, due to corrupted data storage on the single bolus-injection run, discovered at207 post-processing (the patients underwent the scanning). Mean tumor size at baseline was 5.2 cm208 (range, 1.6–9.3 cm). At 2 weeks, mean tumor size was 102% of baseline (100% of baseline209 being no change, standard deviation 22 %). Median PFS was 3.6 months (range, 1.8–17.4210 months; 95% CI: 2.085, 5.115) based on RECIST 1.1 (Edeline et al. 2012). Median OS was 7.1211 months (range, 1.8–27.3 months; 95% CI: 0, 14.270). At the time of analysis, five patients were212 still alive, and OS was assigned as the current duration of therapy.213214 DCE-US Infusion Method10 11215216 Reduction of tumor fractional blood volume (INFBV) using the infusion method at 2 weeks217 occurred in 10/15 (16–81% of baseline, mean 47%) while 5/15 showed an increase (116–535%,218 mean, 220%). (Figure 3.) The Kaplan-Meier analyses for INFBV at 2 weeks and PFS showed no219 statistically significant difference (p = 0.310) but for OS the p-value was borderline (p = 0.050,220 Figure 5). For the clinical outcome of tumor response at 16 weeks, Kaplan-Meier analysis and221 log-rank test also showed no association between INFBV at 2 weeks and progression (p = 0.849).222 (Table 2.)223224 Reduction of infusion tumor blood velocity (INFVM) at 2 weeks occurred in 5/15 (42-98% of225 baseline, mean 83%) while 8/15 showed an increase (1–25% increase from baseline, mean, 9%)226 and there was no change in 2/15 measured. An increase or decrease in INFVM at 2 weeks did not227 correlate to the clinical outcomes of PFS, OS, or treatment response at 16 weeks (analyses not228 shown).229230 DCE-US Bolus Method231232 Reduction of BOLAUC at 2 weeks occurred in 5/12 (11–68% of baseline, mean, 38%) while 7/12233 showed an increase (2–72% increase, mean, 32%). (Figure 4.) The Kaplan-Meier analyses for234 BOLAUC at 2 weeks and PFS or OS showed no statistically significant difference between235 patients that had an increase or decrease in measured tumor perfusion (p = 0.357 and p = 0.711,236 respectively, Figure 5). For the clinical outcome of tumor response at 16 weeks, Kaplan-Meier237 analysis and log-rank test showed no association between BOLAUC at 2 weeks and progression238 (p = 0.369).11 12 239240 The remaining six bolus method perfusion parameters, including BOLPEAK, BOLTTP, BOLAUC-in,241 BOLAUC-out, BOLMTT, and BOLSLOPE, also did not correlate with the clinical outcomes of PFS, OS,242 and tumor response at 16 weeks (analyses not shown).243244245 Liver Perfusion246247 Eight patients had measureable liver bolus data and 11 patients had measureable liver infusion248 data at baseline and at 2 weeks. (Table 3.) Not all patients had visible liver parenchyma in the249 images recorded to evaluate the tumor mass at each time point. Liver function test results were250 available for all patients at 16 weeks. Six of 8 bolus and 10 of 11 infusion patients had251 measurable decrease in BOLAUC or INFBV in liver parenchyma at two weeks (BOLAUC median252 -44%, range -94% to +574%; INFBV median -47%, range -67% to +99%). No patients were253 recorded to have liver adverse events (rise of LFTs, jaundice, or encephalopathy). No patients254 were recorded to have treatment-related liver adverse events. One patient with liver255 decompensation had tumor progression and dehydration and was palliated.256257 DISCUSSION258259 Emerging use of antiangiogenic chemotherapeutics necessitates measurement of treatment260 response by imaging of tumor perfusion, to detect changes in tumor vascularity, rather than261 assess the later change in tumor size (Eisenhauer et al. 2009; Jain et al. 2009; O'Connor et al.262 2008; Turkbey et al. 2009). Axitinib is a novel antiangiogenic agent and is both a potent and263 selective tyrosine kinase inhibitor (TKI). It acts through interrupting pathways for tumor 12 13264 neoangiogenesis, blocking signaling at vascular endothelial cell growth factor receptor265 (VEGFR), platelet-derived growth factor receptor-β (PDGFR-β) and colony stimulating factor-1266 receptor (CSF-1) (Choueiri 2008; Kelly and Rixe 2010; Rugo et al. 2005). It has been studied267 in the treatment of hematologic and solid-organ cancers, including cholangiocarcinoma,268 pancreatic cancer, breast cancer, acute myeloid leukemia and renal cell carcinoma (Rugo et al.269 2005; Takahashi et al. 2014; Wilmes et al. 2007). 270271 Our study is the first to report infusion technique parameters utilizing DCE-US for early272 detection of treatment response to axitinib in patients with advanced HCC. The included patient273 cohort was 2/3 male with the cause of cirrhosis predominantly relating to hepatitis viral274 infection, which is representative of patients referred to a tertiary centre in Canada. Concordant275 with other published studies examining DCE-US perfusion parameters in early detection of276 HCC response to antiangiogenics, we have demonstrated measureable differences in tumor277 perfusion at 2 weeks, a time frame similar to other studies. Our results demonstrate278 measureable changes in HCC tumor perfusion at 2 weeks of therapy with axitinib. Tumor sizes279 remained stable at this early time point (according to RECIST 1.1) but increases or decreases in280 perfusion parameters were measurable. Early detection of response could potentially reassure281 the patient and clinician to persist with therapy. Early detection of non-response could trigger an282 escalation of dose in the absence of concerning toxicity, or discontinue or change therapy in a283 declining patient with troublesome side effects. Treatment-related adverse events were284 commonly seen on this study but usually manageable and some patients could tolerate dose285 escalation (McNamara et al. 2015). There is a growing body of evidence in tyrosine kinase286 inhibitor research that support a more dynamic and individualized patient dosing strategy of287 drug based on biomarkers such as toxicity and imaging (Bjarnason et al. 2015).13 14 288289 In our study, the most promising perfusion parameter on DCE-US to detect response to axitinib290 was INFBV, an initial reduction in tumor perfusion at two weeks seen in patients with increased291 PFS and OS. In our data, tumor blood volume (INFBV) with infusion technique decreased at 2292 weeks in 10/15 (16 - 81% of baseline, mean, 47%) and increased in 5/15 (116 - 535%, mean,293 220%). The association was not significantly correlated with PFS (p = 0.310) or progression at294 16 weeks (p = 0.849) but was borderline statistically significant (P = 0.050) for OS, with the295 small sample size being a limitation. Further studies with a larger patient population are296 required to confirm the utility of this technique in evaluating the usefulness of perfusion297 parameters in DCE-US. Measurable changes in tumor INFBV by the infusion technique have298 been reported in RCC: Williams et al compared bolus and infusion techniques in 17 patients299 with RCC, treated with sunitinib (Williams et al. 2011). DCE-US was performed at 2 weeks and300 compared to imaging using RECIST criteria at 6 weeks, and PFS. The infusion technique301 demonstrated a reduction in median tumor fractional blood volume of 73% at this early time302 point, before a change in perfusion by the bolus method was detected. However, this did not303 predict PFS or RECIST response at 6 weeks. 304305 Our results did not confirm the utility of BOLAUC as a parameter predictive of tumor response306 reported in other studies, but we only had 12 patients with complete bolus data. In contrast,307 there are several prior studies that have reported BOLAUC as a promising imaging parameter to308 predict the patient’s outcome. These studies involved different antiangiogenic agents, using309 different ultrasound contrast agents and equipment. For example, Lassau et al. measured tumor310 response to bevacizumab using the bolus technique in 42 patients with HCC, at days 3, 7, 14311 and 60 of therapy (Lassau et al. 2011). They reported results that trended towards statistical312 significance for prediction of tumor response by BOLAUC, as well as BOLAUC-in and BOLAUC-out 14 15313 and TTP. Frampas et al measured tumor response to sorafenib in 19 patients with HCC using314 the bolus method at one month post commencement of treatment. A decrease of > 40% in315 BOLAUC was reported to predict non-progression by RECIST criteria at two months (Frampas et316 al. 2013). Assunta et al measured tumor response to sorafenib in 28 patients with HCC using the317 bolus method at 15 and 30 days post commencement of treatment, and demonstrated that318 BOLAUC at 15 days predicted tumor response at two months (Assunta et al. 2013).319320 Most patients with measurable liver perfusion demonstrated a decrease in background liver321 perfusion at 2 weeks, measured by both bolus and infusion methods: 6/8 BOLAUC and 11/12322 INFBV; however, this did not correlate to the hepatic adverse events (increased LFT, jaundice, or323 encephalopathy). Sugimoto et al measured tumor response to sorafenib using the bolus method324 in 37 patients with HCC, at days 7, 14 and 28 of treatment (Sugimoto et al. 2013). The BOLAUC325 at day 7 of liver parenchyma predicted adverse events presumed related to drug toxicity on the326 liver. We demonstrated measureable changes in liver parenchyma perfusion parameters with327 both bolus and infusion techniques, but report no adverse events of presumed liver drug328 toxicity.329330 Our study had a number of limitations. This sub-study was limited by a small sample size with331 inability to measure lesions at differing timepoints in a number of patients. Larger study332 population numbers are needed to confirm expected utility for DCE-US in measuring tumor333 response to the novel antiangiogenic agent, axitinib. Also, the clinical endpoint of OS may not334 be the ideal outcome measure to correlate with DEC-US tumor response to axitinib in this study335 population as there are competing causes for mortality, such as liver failure relating to336 background cirrhosis. In addition, as part of this Phase II clinical trial, the enrolment was of a15 16 337 patient group who had failed previous therapy, and whose option was salvage therapy, therefore338 results may compromised. 339340 In summary, INFBV measurement using the DCE-US infusion technique is potentially useful as341 an imaging biomarker to predict OS in patients with advanced HCC who are treated with342 axitinib. Early perfusion reduction of HCC tumors was detected by DCE-US (INFBV) 2 weeks343 after treatment with axitinib in most patients, when tumor size had not changed. A larger study344 is needed to investigate further.34516 17346 FUNDING SUPPORT 347 This was an investigator-initiated study and was funded in part by 348 Pfizer Canada. Dr. Jennifer J. 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Axitinib (AG-013736), an 426 oral specific VEGFR TKI, shows potential therapeutic utility against cholangiocarcinoma. 427 Jpn J Clin Oncol Oxford University Press, 2014;44:570–578. 428 Turkbey B, Kobayashi H, Ogawa M, Bernardo M, Choyke PL. Imaging of Tumor Angiogenesis: 429 Functional or Targeted? AJR Am J Roentgenol 2009;193:304–313. 430 Williams RR, Hudson JMJ, Lloyd BAB, Sureshkumar ARA, Lueck GG, Milot LL, Atri MM, 431 Bjarnason GAG, Burns PNP. Dynamic microbubble contrast-enhanced US to measure tumor 432 response to targeted therapy: a proposed clinical protocol with results from renal cell 433 carcinoma patients receiving antiangiogenic therapy. Radiology 2011;260:581–590. 434 Wilmes LJ, Pallavicini MG, Fleming LM, Gibbs J, Wang D, Li K-L, Partridge SC, Henry RG, 435 Shalinsky DR, Hu-Lowe D, Park JW, McShane TM, Lu Y, Brasch RC, Hylton NM. AG- 436 013736, a novel inhibitor of VEGF receptor tyrosine kinases, inhibits breast cancer growth 437 and decreases vascular permeability as detected by dynamic contrast-enhanced magnetic 438 resonance imaging. Magn Reson Imaging Elsevier, 2007;25:319–327. 43944020 21441 FIGURE LEGENDS442443 Figure 1. DCE-US with Bolus Method and Time-Intensity Curve444 The region-of-interest (ROI) outlines the tumor on simultaneous contrast-ultrasound image445 (left) and B-mode image (right). The intensity of contrast bubbles is plotted against time, with446 the fit curve superimposed. 1. Peak signal intensity (BOLPEAK). 2. Time to peak signal intensity447 (BOLTTP). 3. Area under the curve wash-in (area up to peak, BOLAUC-in). 4. Area under the curve448 wash-out (area after peak, BOLAUC-out). 5. Total area under the curve (BOLAUC) = 3 + 4.449450 Figure 2. DCE-US with Infusion Method and Time-Intensity Curve451 The region-of-interest (ROI) outlines the tumor on simultaneous contrast-ultrasound image452 (left) and B-mode image (right). The intensity of contrast bubbles is plotted against time, with453 the fit curve superimposed. 1. Peak intensity, which reflects fractional blood volume (INFBV).454 2. Slope, which reflects flow velocity (INFVM).455456 Figure 3. Percentage Change of BOLAUC at Two Weeks From Baseline by Patient457458 Figure 4. Percentage Change of INFBV at Two Weeks From Baseline by Patient459460 Figure 5. Kaplan-Meier Analyses for PFS and OS and Patients with Increased or461 Decreased BOLAUC or INFBV at Two Weeks46221 22 463 TABLES464 Table 1. Patient Demographics, Tumor Size, Standard Clinical OutcomesTumo r SizeTumo 2 PFS OS r Size weeks (mont (montSex Age Cause CP (mm) (mm) hs) hs) 1 M 36 Other A5 34 25 2.5 7.1 2 F 22 Hep B A5 58 52 13.2 22.4 3 F 65 Other A5 37 29 12.6 27.3 4 F 18 Hep B A5 36 33 3.6 6.6 5 M 57 Hep C A5 26 43 1.9 6.3 6 F 52 Hep C B7 62 67 12.3 13.7 7 M 75 Hep C B7 45 51 1.8 1.8 Alcoh8 M 69 ol A5 79 72 17.4 17.4 9 M 78 Hep B A5 16 28 4.6 4.6 10 M 50 Hep B A5 37 36 3.4 6.7 11 M 66 Hep B A5 66 68 10.8 10.8 12 M 76 Other A6 91 98 2.6 3.1 13 M 66 Hep B A5 57 67 3.5 8.1 14 F 69 Other A5 47 40 5.9 7.1 Alcoh15 M 55 ol A6 93 97 3.4 3.4 *CP= Childs-Pugh score. PFS = Progression-Free Survival. OS = Overall Survival. 46546622 23467 Table 2. Changes of DCE-US Perfusion Parameters at Two Weeks Compared with Baseline and Clinical OutcomesTUMOR TUMOR TUMOR TUMOR TUMOR TUMOR TUMOR TUMOR TUMOR PFS OSBOLAUC BOLPEAK BOLAUC-IN BOLAUC-OUT BOLTTP BOLMTT BOLSLOPE INFBV INFVM (months) (months) 1 NA NA NA NA NA NA NA -47% 14% 2.5 7.1 2 NA NA NA NA NA NA NA -69% 19% 13.2 22.4 3 2% -14% 544% -69% 575% -11% -84% -29% -4% 12.6 27.3 4 -89% -88% -87% -89% 15% -2% -90% -80% -2% 3.6 6.6 5 17% -39% 241% -7% 461% 165% -80% 49% -14% 1.9 6.3 6 57% 127% 15% 62% -48% -53% 298% -37% 25% 12.3 13.7 7 -45% -31% -58% -42% -32% -29% -31% -51% 0% 1.8 1.8 8 36% 33% 39% 34% -2% 1% 13% -44% 3% 17.4 17.4 9 NA NA NA NA NA NA NA 16% 4% 4.6 4.6 10 -32% -12% 10280% -38% 3650% -3% -88% -19% 0% 3.4 6.7 11 -88% -84% -91% -87% -41% -48% -72% -84% 5% 10.8 10.8 12 7% -8% 10% 6% 17% 30% -11% 436% -10% 2.6 3.1 13 -60% -45% -68% -58% -40% -46% -13% -70% 1% 3.5 8.1 14 72% -56% 202% 66% 517% 803% -90% 75% -58% 5.9 7.1 15 35% 14% 202% 16% 143% -7% -42% 23% 2% 3.4 3.4 NA = Not Available. Values expressed as percentage change from baseline. i.e. no change = 0%, decrease = a negative % and increase = a positive %. PFS = Progression-Free Survival. OS = Overall Survival.23 24468 Table 3. Changes of DCE-US Perfusion Parameters at Two Weeks Compared with Baseline469 and Clinical OutcomesOSLIVER LIVER LIVER PFS (monPt BOLAUC INFBV INFVM (months) ths) 1 NA -35% 5% 2.5 7.1 2 NA NA NA 13.2 22.4 3 NA NA NA 12.6 27.3 4 -93% -59% 33% 3.6 6.6 5 -22% -16% -23% 1.9 6.3 6 574% 99% 7% 12.3 13.7 7 -33% -55% -7% 1.8 1.8 8 -54% -64% 12% 17.4 17.4 9 NA -47% -20% 4.6 4.6 10 NA -4% 1% 3.4 6.7 11 -86% -67% -15% 10.8 10.8 12 NA NA NA 2.6 3.1 13 -68% -57% -2% 3.5 8.1 14 8% -16% 0% 5.9 7.1 15 NA NA NA 3.4 3.4 NA = Not Available. Values expressed as percentage change from baseline. i.e. no change = 0%, decrease = a negative % and increase = a positive %. PFS = Progression-Free Survival. OS = Overall Survival. 470 47124

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