Changes In Tumor Perfusion Research Articles

Imaging with [18f]-fluorodeoxyglucose positron emission tomography (FDG-PET) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) as markers of drug effect in a phase I dose-escalation study of combined RAD 001 and cetuximab.

3048 Background: Preclinical studies suggest that mTOR inhibitors may have both metabolic and anti-angiogenic effects. We employed FDG-PET as a pharmacodynamic marker of mTOR inhibition, and DCE-MRI as an indicator of changes in tumor blood flow in a phase 1 combination study of RAD001 and cetuximab. Methods: 29 patients with EGFR-expressing solid tumors were randomized to a 3-week run-in of single agent RAD001 (30-70 mg PO) or cetuximab (400 mg/m2 IV loading, 250 mg/m2 IV maintenance) weekly, followed by the combination weekly. The primary endpoints were phase II dose finding and toxicity characterization. FDG-PET and DCE-MRI were performed at three time points (baseline, run-in, and combination), to assess for changes in tumor metabolic activity and perfusion, and for subsequent correlation to treatment response (CT or MRI after every two cycles of combination therapy). Results: RAD 001 was tolerated at the highest dose level. Grade 3 or worse toxicity included thrombocytopenia, hypokalemia, elevation in AST and alkaline phosphatase, and skin toxicity. 10 patients were evaluable for response. 5 patients had stable disease lasting 4-19 months (colon, parotid, anal and 2 ovarian). Mean % change in SUVmax from baseline for those treated with RAD001 during run-in (n=12) was -23.4 (range +1.4 to -52.9%), and a dose relationship was evident. The SUV change in pts treated first with cetuximab (n=13) was -9.6% (-53 to +35%). In 10 pts in whom RAD001 was added after cetuximab, there was an additional 11% decrease in SUV, while in patients treated first with RAD001, the SUV change was +12.4%, suggesting that an initial inhibitory effect was being circumvented by the tumor. Mean % change in SUVmax from baseline for the group with SD was lower than in the group with PD. The Ktrans measured by DCE-MRI did not change (-0.9%, n=7), irrespective of run-in drug. Conclusions: Metabolic responses by FDG-PET compared to DCE-MRI changes reveal that the metabolic effects of RAD001 alone and in combination with cetuximab predominate, while antiangiogenic effects appear to be minimal in this patient population.

Abstract 4246: Enhanced anti-vascular and anti-tumor effects upon combination therapy with aflibercept (VEGF Trap) and other anti-angiogenic drugs

Abstract Experimental and clinical development of anti-angiogenic drugs to date has mostly focused on the VEGF pathway, although other signaling pathways, including Dll4-Notch and Angiopoietin-Tie, are now also being explored. Targeting one pathway, however, might not result in maximum anti-vascular and anti-tumor effects. In this study, we compared the rapid effects on tumor perfusion of single agent blockade of VEGF, Dll4 or Ang2 to the effects of combined therapy (VEGF blockade plus either Dll4 or Ang2 blockade), and compared long-term tumor growth responses to these early effects on tumor perfusion. Using aflibercept (VEGF Trap) alone and in combination with a blocking Dll4 antibody or a blocking Ang2 antibody, we compared various tumors with a wide range of long-term growth responses to each agent: C6 rat glioma tumors, HT1080 human fibrosarcoma and Colo205 human colon carcinoma tumors, all grown subcutaneously in SCID/CB17 mice. Tumor vascular perfusion was assessed using contrast-enhanced micro-ultrasound at 24 and 72 hr after treatment. We found that aflibercept treatment rapidly decreased vascular perfusion in C6 (59% after 24 hr) and Colo205 (32%) tumors, whereas there was no decrease observed in HT1080 tumors. These changes in perfusion correlated with long-term tumor growth inhibition upon aflibercept treatment. Dll4 blockade resulted in decreased vascular perfusion in C6 (30% after 24 hr), Colo205 (77%), and HT1080 (54%) tumors, which again correlated with long-term growth inhibition of the different tumors. Treatment with an anti-Ang2 antibody produced a slight decrease in perfusion of Colo205 tumors (13% after 24 hr), associated with a decrease in tumor growth. However, combination treatments with aflibercept plus either anti-Dll4 or anti-Ang2 antibodies were more potent in all tumor types compared to single agent treatments at reducing tumor perfusion as well as inhibiting long-term tumor growth. Taken together, these data show that changes in tumor perfusion correlate with long-term tumor responses to combination treatment of aflibercept plus either anti-Dll4 or anti-Ang2 antibody suggesting that decreases in tumor perfusion could be an early biomarker predictive of response to anti-angiogenic therapies. Measuring the increased effectiveness of combination therapy in patients treated with different anti-angiogenic drugs may facilitate the improvement of current treatment regimens. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4246. doi:10.1158/1538-7445.AM2011-4246

Abstract LB-283: JX-594, a targeted multi-mechanistic oncolytic poxvirus, selectively infects tumor vasculature and causes acute tumor vascular disruption and necrosis in advanced cancer patients

Abstract JX-594 is a first-in-class targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with cell cycle abnormalities and epidermal growth factor receptor (EGFR)/ras pathway activation. Direct oncolysis plus granulocyte macrophage -colony stimulating factor (GM-CSF) expression also stimulates anti-tumoral immunity. JX-594 infection was evaluated in vitro on human umbilical vein endothelial cells (HUVECs) and by immunohistochemical analysis in tumor biopsies from JX-594 treated (intravenous administration) patients with advanced, treatment-refractory solid tumors. JX-594 associated changes in tumor perfusion were also assessed in patients by dynamic contrast-enhanced magnetic resonance imaging (dce-MRI; at baseline and Day 5 after intratumoral JX-594 administration). In vitro susceptibility of HUVECs to JX-594 infection was shown to be dependent on vascular endothelial growth factor (VEGF) stimulation. Furthermore, JX-594 was capable of infecting tumor-associated endothelial cells after intravenous infusion in patients with advanced solid tumors. No clinical evidence of normal vasculature infection or toxicity was noted. Tumor perfusion was significantly decreased within 5 days post JX-594 treatment, including in hepatocellular carcinoma and colorectal cancer metastases. Perfusion was markedly reduced in both directly injected and distant non-injected tumors. Choi (necrotic) responses at later timepoints were demonstrated. In addition to targeting cancers by direct infection and lysis of tumor cells, JX-594 is capable of directly infecting VEGF-stimulated/tumor-associated endothelial cells. By targeting tumor-associated vasculature, JX-594 acutely disrupts the tumor's blood supply leading to tumor destruction. Targeted oncolytic poxviruses such as JX-594 represent a novel and highly selective class of vascular disrupting agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-283. doi:10.1158/1538-7445.AM2011-LB-283

Contrast-enhanced ultrasonic parametric perfusion imaging in the evaluation of antiangiogenic tumor treatment

To assess the validity of contrast-enhanced ultrasonic parametric perfusion imaging in the evaluation of antiangiogenic tumor treatment by using histology as the reference standard. H22 hepatoma-bearing mice were treated with thalidomide or placebo by intraperitoneal injection. Contrast-enhanced ultrasound was performed on day 8 after bolus injection of SonoVue. Three different parametric perfusion images were calculated based on the following parameters: area under the curve (AUC), maximum intensity (IMAX) and perfusion index (PI). A score from 1 to 5 (1 = low, 5 = excellent) was used for analysis of parametric perfusion images by two independent readers. Immunohistochemical analysis was performed for evaluation of microvascular density (MVD). Treatment with thalidomide resulted in a significant decrease in perfusion scores assigned to AUC, IMAX and PI parametric images as compared with control tumors (P < 0.001). Immunohistochemistry showed significant decreases of MVD in treated tumors as compared with control tumors (P = 0.002). MVD was positively correlated with the perfusion scores assigned to AUC parametric images (r = 0.568, P = 0.009), IMAX parametric images (r = 0.614, P = 0.004) and PI parametric images (r = 0.636, P = 0.003). Contrast-enhanced ultrasonic parametric perfusion imaging provides a noninvasive tool to directly visualize tumor perfusion changes after antiangiogenic tumor treatment.

462 Micro-environmental influences on cancer stem cells

To investigate the early effects of a vascular disrupting agent (VDA) in ectopic and orthotopic tumors by using macromolecular contrast media (MMCM)-enhanced magnetic resonance imaging (MMCM-MRI).The MMCM-MRI of ectopic and orthotopic MCA205 murine fibrosarcomas was performed using the intravascular contrast agent albumin-(gadopentetate dimeglumine)35. Change in longitudinal relaxation rate (ΔR1) was measured 24 hours after treatment with 5,6-dimethylxanthenone-4-acetic acid (DMXAA; 30 mg/kg) and used to compute tumor vascular volume and permeability. Correlative histologic and immunohistochemical evaluation was carried out, along with measurement of tumor necrosis factor α and vascular endothelial growth factor levels in whole tumor extracts using the enzyme-linked immunosorbent assay.Orthotopic tumors showed higher vascular volume (p < 0.05) than ectopic tumors before treatment. Twenty-four hours after DMXAA treatment, a significant (p < 0.0001), but differential, decrease in ΔR1 (70% in ectopic and 50% in orthotopic tumors) was observed compared with baseline estimates. Consistent with this observation, greater levels of tumor necrosis factor α, an important mediator of the antivascular activity of DMXAA, were measured in ectopic tumors 3 hours posttreatment compared with orthotopic tumors (p < 0.05). Immunohistochemical (CD31) and histologic (hematoxylin and eosin) sections of ectopic and orthotopic tumors showed highly tumor-selective vascular damage after treatment with the presence of viable surrounding normal tissue.The MMCM-MRI provided early quantitative estimates of change in tumor perfusion after VDA treatment that showed good correlation with cytokine induction. Differences in the response of ectopic and orthotopic tumors highlight the influence of the host microenvironment in modulating the activity of VDAs.

Advanced Hepatocellular Carcinoma: Early Evaluation of Response to Bevacizumab Therapy at Dynamic Contrast-enhanced US with Quantification—Preliminary Results

To investigate whether there is any correlation between standard efficacy endpoints-specifically, tumor response, progression-free survival, and overall survival-and tumor perfusion parameters measured by using dynamic contrast material-enhanced ultrasonography (US) in patients with advanced hepatocellular carcinoma (HCC) treated with bevacizumab. The institutional review board approved the study, and all patients provided written informed consent before their enrollment. Between June 3, 2005, and September 28, 2007, 42 patients (33 men, nine women; median age, 62 years; age range, 23-84 years) participated in this phase II study of single-agent bevacizumab treatment. Tumor response (based on RECIST [response evaluation criteria in solid tumors]) at 2 months was assessed in 37 patients, and progression-free survival and overall survival were assessed in all 42 patients. Dynamic contrast-enhanced US (ie, dynamic US) was performed before treatment (day 0); on days 3, 7, 14, and 60 after treatment; and every 2 months thereafter. Tumor perfusion parameters were estimated quantitatively from contrast material uptake curves constructed from raw linear data. The changes in dynamic US functional parameters between day 0 and the later time points were compared between treatment responders and nonresponders by using nonparametric tests. Given multiple comparisons, P < .001 indicated significance. The percentage decrease in several dynamic US parameters between day 0 and day 3 showed trends toward correlation with (a) tumor response in terms of total area under the time-intensity curve (AUC) (P = .02), AUC during wash in (P = .04), AUC during washout (P = .02), and time to peak intensity (P = .03); (b) progression-free survival in terms of time to peak intensity (P = .028); and (c) overall survival in terms of AUC (P = .002) and AUC during washout (P = .003). Dynamic US can be used to quantify dynamic changes in tumor vascularity as early as 3 days after bevacizumab administration in patients with HCC. These early changes in tumor perfusion may be predictive of tumor response at 2 months, progression-free survival, and overall survival, and they may be potential surrogate measures of the effectiveness of antiangiogenic therapy in patients with HCC.

A phase I study of cediranib plus whole-brain radiation therapy in patients with brain metastases from non-small cell lung cancer.

TPS177 Background: Brain metastases (BM) are common in patients with non-small cell lung cancer (NSCLC), and whole-brain radiation therapy (WBRT) is associated with only modest benefit in many patients and a median survival of 4.5 months. Cediranib is an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor with potent anti-edema effects in glioblastoma patients (Batchelor 2007) and clinical activity in NSCLC when given in combination with chemotherapy (Goss 2010). Preclinical data also suggests that angiogenesis inhibition may potentiate the antitumor effects of radiation (Lee 2000, Winkler 2004, Cao 2006, Dings 2007, Williams 2008). The goal of this phase I study is to establish safety of cediranib when given in combination with WBRT in patients with BM from NSCLC. Methods: Eligibility: newly diagnosed BM; histologically confirmed NSCLC; ≥1 cm measurable disease in brain; no prior therapy for BM; ≥ 12 weeks elapsed since diagnosis of NSCLC; stable primary tumor; no oral anticoagulants; no history of brain hemorrhage or significant hemoptysis; able to undergo magnetic resonance imaging (MRI). Study design: standard 3+3 dose escalation starting at 20 mg oral daily, planned sample size 9-18. Treatment: cediranib 20-45 mg oral daily starting 2 days before WBRT (35Gy in 14 fractions) and continuing until progression at any site. Restaging evaluations of both brain and systemic disease will occur 1 month after completion of WBRT and every 2 months thereafter. Primary endpoint: safety and tolerability. Secondary endpoints: objective response rate in brain, time to neurological progression, overall survival, cause of death. Correlative studies: serial non-invasive vascular MRI (dynamic contrast enhanced MRI, arterial spin labeling and perfusion weighted imaging) will be performed on days -1, 1, 21, 49 to explore changes in tumor perfusion, permeability and blood flow and to define presence or absence of vascular normalization. Current enrollment: Dose level 1 is open for enrollment. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Dyax, Genentech, Millennium, Novartis, Regeneron, SynDevRx SynDevRx Pfizer AstraZeneca, Genentech, Novartis, Takeda

Quantitative 4D transcatheter intraarterial perfusion MRI for monitoring chemoembolization of hepatocellular carcinoma

To develop a fully quantitative 4D transcatheter intraarterial perfusion (TRIP) magnetic resonance imaging (MRI) technique and prospectively test the hypothesis that quantitative 4D TRIP-MRI can be used clinically to monitor intraprocedural liver tumor perfusion reductions during transcatheter arterial chemoembolization (TACE). TACE was performed within an x-ray digital subtraction angiography (DSA)-MRI procedure suite in 16 patients with hepatocellular carcinoma. Quantitative 4D TRIP-MRI with targeted radiofrequency field mapping and dynamic longitudinal relaxation rate mapping was used to monitor changes in tumor perfusion during TACE. First-pass perfusion analysis was performed to produce intraprocedural blood flow (Frho) maps. Mean liver tumor perfusions before and after TACE were compared with a paired t-test (alpha = 0.05). Perfusion reductions were successfully measured with quantitative 4D TRIP-MRI in 22 separate tumors during 18 treatment sessions. Mean tumor perfusion Frho decreased from 16.3 (95% confidence interval [CI]: 10.7-21.9) before TACE to 5.0 (95% CI: 3.5-6.5) (mL/min/100 mL) after TACE. Tumor perfusion reductions were statistically significant (P < 0.0005), with a mean absolute perfusion change of 11.4 (95% CI: 5.6-17.1) (mL/min/100 mL) and a mean percentage reduction of 61.0% (95% CI: 48.3%-73.6%). Quantitative 4D TRIP-MRI can be successfully performed within clinical interventional settings to monitor intraprocedural changes in liver tumor perfusion during TACE.

Abstract 390: Correlation of the effects of antiangiogenic agents aflibercept (VEGF Trap) and anti-Dll4 antibody on tumor vascular perfusion and tumor growth

Abstract Anti-angiogenic treatments are becoming widely used in several major cancer types. Most experimental and clinical development to date has focused on the VEGF pathway, although other signaling pathways, including Dll4-Notch, are also now being explored. However, clinical development for anti-angiogenic therapy has been hindered by a lack of tumor response biomarkers. In this study, we sought to correlate long-term tumor growth responses following blockade of VEGF or Dll4 with rapid effects on tumor vascular perfusion. Using VEGF Trap (aflibercept) and a blocking Dll4 antibody, we compared two tumors that differ widely in their long-term growth responses to each agent: C6 rat glioma tumors (anti-Dll4 resistant, aflibercept sensitive) and HT1080 human fibrosarcoma (anti-Dll4 sensitive, aflibercept resistant), both grown subcutaneously in SCID/CB17 mice. Tumor vascular perfusion was assessed using contrast-enhanced micro-ultrasound at 24 hr after treatment with aflibercept, anti-Dll4 Ab, or the combination, and tumor growth was measured during the course of prolonged twice-weekly treatments. We found that aflibercept treatment rapidly decreased tumor vascular perfusion in C6 tumors (36%) and produced an extended delay in tumor growth (8 days to reach 500mm3). In contrast, anti-Dll4 antibody produced no significant decrease in perfusion of C6 tumors at 24 hr after treatment, and a less dramatic delay in tumor growth (5 days to reach 500mm3). In HT1080 tumors, anti-Dll4 Ab dramatically decreased perfusion (38%), as well as causing a prolonged growth delay (20 days to reach 300mm3), whereas aflibercept caused neither a decrease in perfusion nor growth in these tumors. Unexpectedly, combination treatment with aflibercept and anti-Dll4 was most potent in both tumor types at reducing tumor perfusion and inhibiting tumor growth. Analysis of vascular density by CD31 immunohistochemistry at 24 hr after treatment revealed a decrease in C6 (57% and 31%) and HT1080 (28% and 19%) upon single agent aflibercept and combination treatment, respectively, while anti-Dll4 increased apparent vascular density of C6 tumors (31%) but produced no change in HT1080 tumors. Taken together, these data show that changes in tumor perfusion, but not in vessel density, correlate with long-term tumor responses to aflibercept and anti-Dll4, thus suggesting that decreases in tumor perfusion could be a rapid response biomarker for efficacy of anti-angiogenic therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 390.

Assessing Early Vascular Changes and Treatment Response After Laser-Induced Thermotherapy of Pulmonary Metastases With Perfusion CT: Initial Experience

The objective of our study was to use perfusion CT to prospectively monitor early vascular changes in tumor perfusion of pulmonary metastases after laser-induced thermotherapy (LITT) and to determine whether any of the perfusion parameters would predict technical success after therapy. Twelve patients with histologically proven pulmonary metastases undergoing LITT were enrolled prospectively in this study. Perfusion CT was performed before treatment, 1 day after treatment, and 4-6 weeks after therapy, and tumor blood flow, tumor blood volume (TBV), mean transit time (MTT), and permeability of the capillary wall surface (capillary permeability-surface product) in 22 pulmonary metastases were calculated. Perfusion parameters at baseline and after LITT were compared. Measurement of tumor diameter on long-term follow-up CT was the gold standard with which perfusion CT results were compared for local control. Median tumor blood flow, TBV, and capillary permeability-surface product had decreased significantly from baseline by 43%, 61%, and 73%, respectively, 1 day after LITT. Perfusion parameters obtained 4-6 weeks after treatment had not changed significantly compared with those obtained 1 day after therapy. There seems to be a good correlation between changes in perfusion CT parameters 1 day after therapy and local outcome, according to the Response Evaluation Criteria in Solid Tumors (RECIST), 1 year after therapy. Perfusion CT of pulmonary metastases has potential in the assessment of early vascular changes that result from LITT and predicting technical success immediately after treatment. Tumors with perfusion measurements that had not changed after therapy indicated progressive disease.

Abstract No. 270: Validation of a subjective angiographic chemoembolization endpoint scale by comparison with quantitative 4D TRIP-MR imaging

Abstract No. 270: Validation of a subjective angiographic chemoembolization endpoint scale by comparison with quantitative 4D TRIP-MR imaging

The effect of mild temperature hyperthermia on tumour hypoxia and blood perfusion: relevance for radiotherapy, vascular targeting and imaging

Clinically achievable mild temperature local hyperthermia (<43°C) has been demonstrated to be an effective adjuvant to radiotherapy in pre-clinical and clinical studies. In this article, we briefly review the recent progress in the following areas: (1) the effect of mild temperature hyperthermia (MTH) on tumour hypoxia and blood perfusion as assessed by dual marker immunohistochemistry (IHC); (2) the kinetics of MTH induced changes in tumour hypoxia; (3) the potential role of heat-induced tumour reoxygenation on radio- and chemo-sensitisation; (4) the potential role of MTH in combination with vascular targeting agents (VTAs) on tumour response; and (5) non-invasive detection of changes in tumour oxygenation and blood perfusion. It is shown that MTH, by itself or in combination with VTAs, leads to changes in tumour perfusion and oxygenation with potential for radio- and chemo-sensitisation.

Decrease in Tumor Cell Oxygen Consumption after Treatment with Vandetanib (ZACTIMA™; ZD6474) and its Effect on Response to Radiotherapy

We investigated the early effects of vandetanib (ZACTIMA; ZD6474), an inhibitor of VEGFR-dependent angiogenesis, on tumor oxygenation and on the possible consequences of combining vandetanib with radiotherapy. Tumor oxygenation, perfusion, cellular consumption of oxygen, and radiation sensitivity were studied in transplantable liver tumors after daily doses of vandetanib (25 mg kg(-1) i.p.). Measurements of oxygenation (pO(2)) and tumor cell oxygen consumption were carried out using electron paramagnetic resonance (EPR), and perfusion parameters were assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Regrowth delay assays were performed after treatment with vandetanib alone, radiation alone or a combination of both treatments. Vandetanib induced an early increase in tumor oxygenation that did not correlate with remodeling of the tumor vasculature or with changes in tumor perfusion. A decrease in tumor cell oxygen consumption was observed that could have been responsible for this increase in tumor oxygenation. Consistent with this increase in tumor oxygenation, we found that vandetanib potentiated the tumor response to radiotherapy. Our results confirm that treatment with an inhibitor of VEGFR signaling reduces oxygen consumption rate by tumor cells. The observation that vandetanib causes an early increase in tumor oxygenation has implications for the timing and sequencing of treatment with VEGF signaling inhibitors in combination with radiation.

Tumor Response in Patients With Advanced Non–Small Cell Lung Cancer: Perfusion CT Evaluation of Chemotherapy and Radiation Therapy

The objectives of this study were to prospectively evaluate changes in tumor perfusion after chemoradiation therapy and to investigate the feasibility of perfusion CT for prediction of early tumor response and prognosis of non-small cell lung cancer. Perfusion CT was performed on an MDCT scanner with 50 mL of iodinated contrast material injected at 4 mL/s. The quality of each functional map was rated from 0 to 3 for 123 patients with confirmed lung cancer. A subset of images was independently reviewed by two radiologists to measure interobserver and intraobserver variability. Perfusion parameters and tumor response were assessed for 35 patients with non-small cell lung cancer who underwent chemoradiation therapy. Progression-free survival and overall survival were analyzed for 22 patients who underwent repeated perfusion CT after therapy. Image quality was graded 2 (moderate) or 3 (good) in 68.2% of cases. High interobserver and intraobserver correlations of perfusion parameters were found on qualified images. The patients who responded to chemoradiation therapy had significantly greater blood flow (p = 0.023) than patients who did not respond. The median progression-free survival period of the patients with an increased permeability-surface area product was 4.7 months, significantly lower than the median progression-free survival period of 19.0 months among patients with a decreased permeability-surface area product (p < 0.001). The median overall survival period was 10.6 months for the group with an increased permeability-surface area product, significantly lower than the 19.3 months for the group with a decreased permeability-surface area product (p = 0.004). Non-small cell lung cancer with higher perfusion is more sensitive to chemoradiation therapy than that with lower perfusion. After chemoradiation therapy, findings at perfusion CT are a significant predictor of early tumor response and overall survival among patients with non-small cell lung cancer.

Longitudinal Changes in Tumor Perfusion Pattern during the Radiation Therapy Course and its Clinical Impact in Cervical Cancer

To study the temporal changes of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion patterns during the radiation therapy (RT) course and their influence on local control and survival in cervical cancer. DCE-MRI was performed in 98 patients with Stage IB(2)-IVA cervical cancer before RT (pre-RT) and during early RT (20-25 Gy) and mid-RT (45-50 Gy). Signal intensity (SI) from the DCE-MRI time-SI curve was derived for each tumor voxel. The poorly perfused low-DCE tumor subregions were quantified as lower 10th percentiles of SI (SI10). Local control, disease-specific survival, and overall survival were correlated with DCE parameters at pre-RT, early RT, and mid-RT. Median follow-up was 4.9 (range, 0.2-9.0) years. Patients (16/98) with initial pre-RT high DCE (SI10 >or=2.1) had 100% 5-year local control, 81% disease-specific survival, and 81% overall survival, compared with only 79%, 61%, and 55%, respectively, in patients with pre-RT low DCE. Conversion from pre-RT low DCE to high DCE in early RT (28/82 patients) was associated with higher local control, disease-specific survival, and overall survival (93%, 74%, and 67%, respectively). In comparison with all other groups, outcome was worst in patients with persistently low DCE from pre-RT throughout the mid-RT phase (66%, 44%, and 43%; p = 0.003, 0.003, and 0.020; respectively). Longitudinal tumor perfusion changes during RT correlate with treatment outcome. Persistently low perfusion in pre-RT, early RT, and mid-RT indicates a high risk of treatment failure, whereas outcome is favorable in patients with initially high perfusion or subsequent improvements of initially low perfusion. These findings likely reflect reoxygenation and may have potential for noninvasive monitoring of intra-treatment radio-responsiveness and for guiding adaptive therapy.

Detecting Vascular-Targeting Effects of the Hypoxic Cytotoxin Tirapazamine in Tumor Xenografts Using Magnetic Resonance Imaging

To determine whether vascular-targeting effects can be detected in vivo using magnetic resonance imaging (MRI). MR images of HCT-116 xenograft-bearing mice were acquired at 7 Tesla before and 24 hours after intraperitoneal injections of tirapazamine. Quantitative dynamic contrast-enhanced MRI analyses were performed to evaluate changes in tumor perfusion using two biomarkers: the volume transfer constant (K(trans)) and the initial area under the concentration-time curve (IAUC). We used novel implanted fiducial markers to obtain cryosections that corresponded to MR image planes from excised tumors; quantitative immunohistochemical mapping of tumor vasculature, perfusion, and necrosis enabled correlative analysis between these and MR images. Conventional histological analysis showed lower vascular perfusion or greater amounts of necrosis in the central regions of five of eight tirapazamine-treated tumors, with three treated tumors showing no vascular dysfunction response. MRI data reflected this result, and a striking decrease in both K(trans) and IAUC values was seen with the responsive tumors. Retrospective evaluation of pretreatment MRI parameters revealed that those tumors that did not respond to the vascular-targeting effects of tirapazamine had significantly higher pretreatment K(trans) and IAUC values. MRI-derived parameter maps showed good agreement with histological tumor mapping. MRI was found to be an effective tool for noninvasively monitoring and predicting tirapazamine-mediated central vascular dysfunction.

Application of perfusion CT scan in assessing the treatment and predicting prognosis for lung cancer before and after chemotherapy/radiotherapy

This study is to evaluate the changes in tumor perfusion CT before and after chemotherapy/radiotherapy, and its feasibility in assessing early treatment response and predicting the prognosis in lung cancer patients. Perfusion CT scan was performed on a multidetector CT scanner with power injection of contrast medium (50 ml, 300 mg I/ml, 4 ml/s) in the patients before and after chemotherapy/radiotherapy. The treatment response after chemotherapy/radiotherapy was assessed by RECIST. The correlation of pre- and post-treatment tumor perfusion changes with progression-free survival (PFS) and overall survival (OS) was analyzed. The patients were divided into two groups according to PS changs. In the increased PS group (n = 13), the PS after treatment was significantly higher than that before treatment (20.1 +/- 7.5 ml x min(-1) x 100 g(-1) vs. 13.7 +/- 6.2 ml/min/100 g, P = 0.013), while in the decreased PS group (n = 11), the PS after treatment was significantly lower than that before treatment (8.2 +/- 5.5 ml x min (-1) x 100 g(-1) vs. 15.3 +/- 5.1 ml x min(-1) x 100 g(-1), P = 0.000). No significant differences were observed in BF, BV, and MTT in both groups. The median PFS of PS increased group and decreased groups was 4.2 months and 19.0 months, respectively, (P = 0.000), and the median OS was 7.9 months and 19.3 months, respectively (P = 0.002). Perfusion CT may have a potential application in predicting the prognosis of lung cancer after chemotherapy/radiotherapy, and PS increase after treatment may indicate a poor survival.

Vasomodulation of Tumor Blood Flow: Effect on Perfusion and Thermal Ablation Size

Blood flow is a key factor in the efficacy of radiofrequency (RF) ablation treatment of solid tumors. We hypothesized that vasoactive drugs can modulate tumor blood flow and thereby improve the outcome of this thermal ablation approach. To verify this hypothesis, we measured the tumor perfusion changes in response to phenylephrine (PE) and hydralazine (HYZ) using a CT perfusion method in a rat subcutaneous tumor model. The coagulation sizes induced by RF ablation alone, RF ablation with PE and RF ablation with HYZ were compared. Results demonstrated that HYZ produced a marked decrease in entire tumor and tumor rim blood flow of 31.1 and 29.1%; while PE insignificantly change tumor blood flow (5.1% decrease in whole tumor and 6.0% decrease in tumor rim). A markedly greater coagulation area (0.59 cm2 +/- 0.24) was observed when HYZ was administered before RF ablation. No difference was noted in the coagulation area induced by RF ablation alone or the combination of PE injection followed by RF ablation (0.29 cm2 +/- 0.13 vs. 0.30 cm2 +/- 0.18). Results suggest that HYZ decreases subcutaneous tumor blood flow and enhances the coagulation size induced by RF ablation. PE has little influence on tumor blood flow and does not improve ablation.

Assessment of the Early Effects of 5,6-Dimethylxanthenone-4-Acetic Acid Using Macromolecular Contrast Media–Enhanced Magnetic Resonance Imaging: Ectopic Versus Orthotopic Tumors

To investigate the early effects of a vascular disrupting agent (VDA) in ectopic and orthotopic tumors by using macromolecular contrast media (MMCM)-enhanced magnetic resonance imaging (MMCM-MRI). The MMCM-MRI of ectopic and orthotopic MCA205 murine fibrosarcomas was performed using the intravascular contrast agent albumin-(gadopentetate dimeglumine)(35). Change in longitudinal relaxation rate (DeltaR1) was measured 24 hours after treatment with 5,6-dimethylxanthenone-4-acetic acid (DMXAA; 30 mg/kg) and used to compute tumor vascular volume and permeability. Correlative histologic and immunohistochemical evaluation was carried out, along with measurement of tumor necrosis factor alpha and vascular endothelial growth factor levels in whole tumor extracts using the enzyme-linked immunosorbent assay. Orthotopic tumors showed higher vascular volume (p < 0.05) than ectopic tumors before treatment. Twenty-four hours after DMXAA treatment, a significant (p < 0.0001), but differential, decrease in DeltaR1 (70% in ectopic and 50% in orthotopic tumors) was observed compared with baseline estimates. Consistent with this observation, greater levels of tumor necrosis factor alpha, an important mediator of the antivascular activity of DMXAA, were measured in ectopic tumors 3 hours posttreatment compared with orthotopic tumors (p < 0.05). Immunohistochemical (CD31) and histologic (hematoxylin and eosin) sections of ectopic and orthotopic tumors showed highly tumor-selective vascular damage after treatment with the presence of viable surrounding normal tissue. The MMCM-MRI provided early quantitative estimates of change in tumor perfusion after VDA treatment that showed good correlation with cytokine induction. Differences in the response of ectopic and orthotopic tumors highlight the influence of the host microenvironment in modulating the activity of VDAs.

Four-dimensional transcatheter intraarterial perfusion (TRIP)-MRI for monitoring liver tumor embolization in VX2 rabbits

Transcatheter intraarterial perfusion (TRIP)-MRI is an intraprocedural technique to iteratively monitor liver tumor perfusion changes during transcatheter arterial embolization (TAE) and chemoembolization (TACE). However, previous TRIP-MRI approaches using two-dimensional (2D) T(1)-weighted saturation-recovery gradient-recalled echo (GRE) sequences provided only limited spatial coverage and limited capacity for accurate perfusion quantification. In this preclinical study, a quantitative 4D TRIP-MRI technique (serial iterative 3D volumetric perfusion imaging) with rigorous radiofrequency (RF) B(1) field calibration and dynamic tissue longitudinal relaxation rate R(1) measurement is presented for monitoring intraprocedural liver tumor perfusion during TAE. 4D TRIP-MRI and TAE were performed in five rabbits with eight VX2 liver tumors (N = 8). After B(1) calibrated baseline and dynamic R(1) quantification, subsequent tissue contrast agent concentration time curves were derived. A single-input flow-limited pharmacokinetic model and peak gradient method were applied for perfusion analysis. The perfusion Frho reduced significantly from pre-TAE 0.477 (95% confidence interval [CI]: 0.384-0.570) to post-TAE 0.131 (95% CI: 0.080-0.183 ml/min/ml, P < 0.001).