J. James Stirling

Combretastatin A4 Phosphate Has Tumor Antivascular Activity in Rat and Man as Demonstrated by Dynamic Magnetic Resonance Imaging

PURPOSE Combretastatin A4 phosphate (CA4P) is a novel vascular targeting agent. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) studies were performed to examine changes in parameters related to blood flow and vascular permeability in tumor and normal tissue after CA4P treatment. MATERIALS AND METHODS Changes in kinetic DCE-MRI parameters (transfer constant [Ktrans] and area under contrast medium-time curve [AUC]) over 24 hours after treatment with CA4P were measured in 18 patients in a phase I trial and compared with those obtained in the rat P22 carcinosarcoma model, using the same imaging technique. Rats were treated with 30 mg/kg of CA4P; patients received escalating doses from 5 to 114 mg/m2. RESULTS A similar pattern and time course of change in tumor and normal tissue parameters was seen in rats and humans. Rat tumor Ktrans was reduced by 64% 6 hours after treatment with CA4P (30 mg/kg). No significant reductions in kidney or muscle parameters were seen. Significant reductions were seen in tumor Ktrans in six of 16 patients treated at >or= 52 mg/m2, with a significant group mean reduction of 37% and 29% at 4 and 24 hours, respectively, after treatment. The mean reduction in tumor initial area under the gadolinium-diethylenetriamine pentaacetic acid concentration-time curve (AUC) was 33% and 18%, respectively, at these times. No reduction was seen in muscle Ktrans or in kidney AUC in group analysis of the clinical data. CONCLUSION CA4P acutely reduces Ktrans in human as well as rat tumors at well-tolerated doses, with no significant changes in kidney or muscle, providing proof of principle that this drug has tumor antivascular activity in rats and humans.

Early Changes in Functional Dynamic Magnetic Resonance Imaging Predict for Pathologic Response to Neoadjuvant Chemotherapy in Primary Breast Cancer

Purpose: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows noninvasive, in vivo measurements of tissue microvessel perfusion and permeability. We examined whether DCE-MRI done after two cycles of neoadjuvant chemotherapy could predict final clinical and pathologic response in primary breast cancers. Experimental Design: Thirty-seven patients with primary breast cancer, due to receive six cycles of neoadjuvant 5-fluorouracil, epirubicin and cyclophosphamide chemotherapy, were examined using DCE-MRI before neoadjuvant chemotherapy and after two cycles of treatment. Changes in DCE-MRI kinetic parameters (Ktrans, kep, ve, MaxGd, rBV, rBF, MTT) were correlated with the final clinical and pathologic response to neoadjuvant chemotherapy. Test-retest variability was used to determine individual patient response. Results: Twenty-eight patients were evaluable for response (19 clinical responders and 9 nonresponders; 11 pathologic responders and 17 nonresponders). Changes in the DCE-MRI kinetic parameters Ktrans, kep, MaxGd, rBV, and rBF were significantly correlated with both final clinical and pathologic response (P < 0.01). Change in Ktrans was the best predictor of pathologic nonresponse (area under the receiver operating characteristic curve, 0.93; sensitivity, 94%; specificity, 82%), correctly identifying 94% of nonresponders and 73% of responders. Change in MRI-derived tumor size did not predict for pathologic response. Conclusion: Changes in breast tumor microvessel functionality as depicted by DCE-MRI early on after starting anthracycline-based neoadjuvant chemotherapy can predict final clinical and pathologic response. The ability to identify nonresponders early may allow the selection of patients who may benefit from a therapy change.

BOLD MRI of human tumor oxygenation during carbogen breathing

An MRI method is described for demonstrating improved oxygenation of human tumors and normal tissues during carbogen inhalation (95% O2, 5% CO2). T  *2 ‐weighted gradient‐echo imaging was performed before, during, and after carbogen breathing in 47 tumor patients and 13 male volunteers. Analysis of artifacts and signal intensity was performed. Thirty‐six successful tumor examinations were obtained. Twenty showed significant whole‐tumor signal increases (mean 21.0%, range 6.5–82.4%), and one decreased (−26.5 ± 8.0%). Patterns of signal change were heterogeneous in responding tumors. Five of 13 normal prostate glands (four volunteers and nine patients with nonprostatic tumors) showed significant enhancement (mean 11.4%, range 8.4–14.0%). An increase in brain signal was seen in 11 of 13 assessable patients (mean 8.0 ± 3.7%, range 5.0–11.7%). T  *2 ‐weighted tumor MRI during carbogen breathing is possible in humans. High failure rates occurred due to respiratory distress. Significant enhancement was seen in 56%, suggesting improved tissue oxygenation and blood flow, which could identify these patients as more likely to benefit from carbogen radiosensitization. J. Magn. Reson. Imaging 2001;14:156–163.

Phase I trial of combretastatin A4 phosphate (CA4P) in combination with bevacizumab in patients with advanced cancer.

Purpose: The vascular disrupting agent (VDA) combretastatin A4 phosphate (CA4P) induces significant tumor necrosis as a single agent. Preclinical models have shown that the addition of an anti-VEGF antibody to a VDA attenuates the revascularization of the surviving tumor rim and thus significantly increases antitumor activity. Experimental Design: Patients with advanced solid malignancies received CA4P at 45, 54, or 63 mg/m2 on day 1, day 8, and then every 14 days. Bevacizumab 10 mg/kg was given on day 8 and at subsequent cycles four hours after CA4P. Functional imaging with dynamic contrast enhanced-MRI (DCE-MRI) was conducted at baseline, after CA4P alone, and after cycle 1 CA4P + bevacizumab. Results: A total of 63 mg/m2 CA4P + 10 mg/kg bevacizumab q14 is the recommended phase II dose. A total of 15 patients were enrolled. Dose-limiting toxicities were grade III asymptomatic atrial fibrillation and grade IV liver hemorrhage in a patient with a history of hemorrhage. Most common toxicities were hypertension, headache, lymphopenia, pruritus, and pyrexia. Asymptomatic electrocardiographic changes were seen in five patients. Nine of 14 patients experienced disease stabilization. A patient with ovarian cancer had a CA125 response lasting for more than a year. DCE-MRI showed statistically significant reductions in tumor perfusion/vascular permeability, which reversed after CA4P alone but which were sustained following bevacizumab. Circulating CD34+ and CD133+ bone marrow progenitors increased following CA4P as did VEGF and granulocyte colony-stimulating factor levels. Conclusions: CA4P in combination with bevacizumab appears safe and well tolerated in this dosing schedule. CA4P induced profound vascular changes, which were maintained by the presence of bevacizumab. Clin Cancer Res; 18(12); 3428–39. ©2012 AACR.

Use of Dynamic Contrast-enhanced MR Imaging to Predict Survival in Patients with Primary Breast Cancer Undergoing Neoadjuvant Chemotherapy

PURPOSE To investigate whether early changes in vascular parameters determined with dynamic contrast material-enhanced magnetic resonance (MR) imaging after two cycles of neoadjuvant chemotherapy (NAC) are predictive of disease-free and overall survival in primary breast cancer. MATERIALS AND METHODS Institutional ethics approval and informed consent were obtained. Patients with primary breast cancer (median age, 45 years; age range, 22-70 years) recruited from January 2001 to September 2008 underwent dynamic contrast-enhanced MR imaging before and after two cycles of NAC. Quantitative and semiquantitative kinetic parameters were calculated, including the volume transfer constant (K(trans)) and the initial area under the gadolinium concentration-time curve over 60 seconds (IAUGC(60)). Cut points optimized to the receiver operating characteristic curve were used to dichotomize MR imaging data for Kaplan-Meier survival analysis. MR imaging parameters and known prognostic indicators in primary breast cancer were correlated with disease-free and overall survival by using the Cox proportional hazards model for univariate and multivariate analyses. RESULTS MR imaging was performed before (n = 62) and after (n = 58) two cycles of NAC. The median follow-up time was 43.9 months for disease-free survival and 60.3 months for overall survival. There were 28 recurrences; 26 patients had distant metastases (two had additional local recurrence) and two had local recurrence only. There were 20 deaths, all of which were related to breast cancer. At univariate analysis, progesterone receptor status, the type of surgery performed, higher posttreatment K(trans) (P = .048), and larger posttreatment IAUGC(60) (P = .035) were significant predictors of worse disease-free survival. At multivariate analysis, progesterone receptor status (P = .002) and mean transit time (P = .025) were significant predictors of disease-free survival. Univariate analysis showed that clinical tumor stage (P = .005), progesterone receptor status (P = .025), and type of surgery performed (P = .017) were significant predictors of overall survival. Higher posttreatment K(trans) (P = .043), larger IAUGC(60) (P = .029), and larger tumor size at posttreatment MR imaging were predictive of worse overall survival (P = .018). Of these variables, K(trans) remained an independent indicator of overall survival (P = .038). CONCLUSION Higher posttreatment tumor vascularization as depicted with dynamic contrast-enhanced MR imaging may be associated with higher recurrence and lower survival rates. Dynamic contrast-enhanced MR imaging parameters, in conjunction with traditional prognostic factors, have the potential to be prognostic biomarkers for disease-free and overall survival in primary breast cancer.

Dynamic contrast-enhanced magnetic resonance imaging is a poor measure of rectal cancer angiogenesis†‡

The aim of this study was to investigate the use of magnetic resonance imaging (MRI) for non‐invasive measurement of rectal cancer angiogenesis and hypoxia.

Vascular characterisation of triple negative breast carcinomas using dynamic MRI

ObjectivesTriple-negative (ER-/PR-/HER2-) breast carcinomas (TNBC) are aggressive tumours with underexplored imaging features. This study investigates whether their vascular characteristics as assessed by dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast-enhanced (DSC) MRI are distinct from the prognostically more favourable ER+/PR+/HER2- cancers.MethodsPatients with primary breast cancer underwent MRI before neoadjuvant chemotherapy and were identified as ER-/PR-/HER2- or ER+/PR+/HER2- from core biopsy specimens. MRI parameters reflecting tissue perfusion, permeability, and extracellular leakage space were measured. Values for inflow transfer constant (Ktrans), outflow rate constant (kep), leakage space (ve), area under the gadolinium curve (IAUGC60 ), relative blood volume (rBV) and flow (rBF), and Mean Transit Time (MTT) were compared across receptor status and with known prognostic variables.ResultsThirty seven patients were assessable in total (16 ER-/PR-/HER2-, 21 ER+/PR+/HER2-). Lower ve (p = 0.001), shorter MTT (p = 0.007) and higher kep values (p = 0.044) were observed in TNBC. ve was lower across all T stages, node-negative (p = 0.004) and low-grade TNBC (p = 0.037). ve was the best predictor of triple negativity (ROC AUC 0.80).ConclusionsTNBC possess characteristic features on imaging, with lower extracellular space (higher cell density) and higher contrast agent wash-out rate (higher vascular permeability) suggesting a distinctive phenotype detectable by MRI.

Dynamic MRI for imaging tumor microvasculature: Comparison of susceptibility and relaxivity techniques in pelvic tumors

To assess the reproducibility of intrinsic relaxivity and both relaxivity‐ and susceptibility‐based dynamic contrast enhanced (DCE) MRI in pelvic tumors; to correlate kinetic parameters obtained and to assess whether acute antivascular effects are seen in response to cisplatin‐ or taxane‐based chemotherapy.

Primary Human Breast Adenocarcinoma: Imaging and Histologic Correlates of Intrinsic Susceptibility-weighted MR Imaging before and during Chemotherapy

PURPOSE To investigate the histopathologic and dynamic magnetic resonance (MR) imaging correlates of intrinsic susceptibility-weighted (ISW) MR imaging in patients with primary human breast adenocarcinoma and to assess the relationship between baseline transverse relaxation rate (R2*) and T2* relaxivity change (ΔR2*) and the response to neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS Institutional ethics approval and informed consent were obtained. Between September 2001 and January 2008, 83 women (median age, 46 years; age range, 26-72 years) with breast cancer were recruited to undergo dynamic contrast medium-enhanced (DCE), dynamic susceptibility contrast-enhanced (DSC), and ISW MR imaging before and after two cycles of NAC. After excluding necrotic, infiltrating, and invasive lobular carcinomas, 31 patients were available for baseline assessment and 27 were available for response assessment. Transfer constant, leakage space, rate constant, initial area under the gadolinium concentration-time curve at 60 seconds, relative blood volume (rBV), relative blood flow (rBF), and R2* were calculated. Relationships between baseline R2* and histopathologic variables (tumor grade, estrogen receptor status, progesterone receptor status, human epidermal growth factor 2 status), tumor size, and dynamic MR imaging parameters were sought. Baseline adenocarcinoma R2* (n = 31) and ΔR2* (n = 27) were correlated with final pathologic response. RESULTS Inverse correlations between baseline R2* and rBV (ρ = -0.48, P = .013) and rBF (ρ = -0.44, P = .024) were found, but not after NAC. No relationships were observed between baseline R2* and other kinetic imaging parameters, histopathologic characteristics, or tumor size (P > .05). Baseline R2* values were lower in tumors than in normal breast tissue (31.8 sec(-1) vs 36.2 sec(-1), P = .017) but not after NAC. Increases in R2* were observed after treatment (31.1 sec(-1) vs 34.8 sec(-1), P = .006), with larger increases correlating with pathologic response. ΔR2* was not as effective as DCE or DSC MR imaging parameters in the prediction of response. CONCLUSION R2* is influenced by blood volume in untreated breast adenocarcinomas. Increases in R2* after two cycles of NAC correlate with pathologic response. Therapy-induced uncoupling of the relationship between R2* and rBV and rBF is consistent with responding tumors becoming hypoxic early during treatment. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100421/-/DC1.

Carbogen breathing increases prostate cancer oxygenation: a translational MRI study in murine xenografts and humans

Hypoxia has been associated with poor local tumour control and relapse in many cancer sites, including carcinoma of the prostate. This translational study tests whether breathing carbogen gas improves the oxygenation of human prostate carcinoma xenografts in mice and in human patients with prostate cancer. A total of 23 DU145 tumour-bearing mice, 17 PC3 tumour-bearing mice and 17 human patients with prostate cancer were investigated. Intrinsic susceptibility-weighted MRI was performed before and during a period of carbogen gas breathing. Quantitative R2* pixel maps were produced for each tumour and at each time point and changes in R2* induced by carbogen were determined. There was a mean reduction in R2* of 6.4% (P=0.003) for DU145 xenografts and 5.8% (P=0.007) for PC3 xenografts. In all, 14 human subjects were evaluable; 64% had reductions in tumour R2* during carbogen inhalation with a mean reduction of 21.6% (P=0.0005). Decreases in prostate tumour R2* in both animal models and human patients as a result of carbogen inhalation suggests the presence of significant hypoxia. The finding that carbogen gas breathing improves prostate tumour oxygenation provides a rationale for testing the radiosensitising effects of combining carbogen gas breathing with radiotherapy in prostate cancer patients.