Exploratory study of using Magnetic resonance Prognostic Imaging markers for Radiotherapy In Cervix cancer (EMPIRIC): a prospective cohort study protocol.

INTRODUCTION: Radical chemoradiotherapy represents the gold standard for locally advanced cervical cancer. However, despite significant progress in improving local tumour control, distant relapse continues to impact overall survival. The development of predictive and prognostic biomarkers is consequently important to risk-stratify patients and identify populations at higher risk of poorer treatment response and survival outcomes. Exploratory study of using Magnetic resonance Prognostic Imaging markers for Radiotherapy In Cervix cancer (EMPIRIC) is a prospective exploratory cohort study, which aims to investigate the role of multiparametric functional MRI (fMRI) using diffusion-weighed imaging (DWI), dynamic contrast-enhanced (DCE) and blood oxygen level-dependent imaging (BOLD) MRI to assess treatment response and predict outcomes in patients undergoing radical chemoradiotherapy for cervical cancer. METHODS AND ANALYSIS: The study aims to recruit 40 patients across a single-centre over 2 years. Patients undergo multiparametric fMRI (DWI, DCE and BOLD-MRI) at three time points: before, during and at the completion of external beam radiotherapy. Tissue and liquid biopsies are collected at diagnosis and post-treatment to identify potential biomarker correlates against fMRI. The primary outcome is to evaluate sensitivity and specificity of quantitative parameters derived from fMRI as predictors of progression-free survival at 2 years following radical chemoradiotherapy for cervical cancer. The secondary outcome is to investigate the roles of fMRI as predictors of overall survival at 2 years and tumour volume reduction across treatment. Statistical analyses using regression models and survival analyses are employed to evaluate the relationships between the derived parameters, treatment response and clinical outcomes. ETHICS AND DISSEMINATION: The EMPIRIC study received ethical approval from the NHS Health Research Authority (HRA) on 14 February 2022 (protocol number RD2021-29). Confidentiality and data protection measures are strictly adhered to throughout the study. The findings of this study will be disseminated through peer-reviewed publications and scientific conferences, aiming to contribute to the growing body of evidence on the use of multiparametric MRI in cervical cancer management. TRIAL REGISTRATION NUMBER: NCT05532930.

Reirradiation Options for Previously Irradiated Prostate cancer (RO-PIP): Feasibility study investigating toxicity outcomes following reirradiation with stereotactic body radiotherapy (SBRT) versus high-dose-rate brachytherapy (HDR-BT).

INTRODUCTION: Radiotherapy is the most common curative treatment for non-metastatic prostate cancer; however, up to 13% of patients will develop local recurrence within 10 years. Patients can undergo further and potentially curative treatment including salvage surgery, brachytherapy (BT), external beam radiotherapy, high-intensity focused ultrasound and cryotherapy. Systematic review shows that high-dose-rate (HDR) BT and stereotactic body radiotherapy (SBRT) have the best outcomes in terms of biochemical control and lowest side effects. The reirradiation options for previously irradiated prostate cancer (RO-PIP) trial aims to determine the feasibility of recruitment to a trial randomising patients to salvage HDR-BT or SBRT and provide prospective data on patient recorded toxicity outcomes that will inform a future phase III trial. METHODS AND ANALYSIS: The primary endpoint of the RO-PIP feasibility study is to evaluate the patient recruitment potential over 2 years to a trial randomising to either SBRT or HDR-BT for patients who develop local recurrence of prostate cancer following previous radiation therapy. The aim is to recruit 60 patients across 3 sites over 2 years and randomise 1:1 to SBRT or HDR-BT. Secondary objectives include recording clinician and patient-reported outcome measures to evaluate treatment-related toxicity. In addition, the study aims to identify potential imaging, genomic and proteomic biomarkers that are predictive of toxicity and outcome based on hypoxia status, a prognostic marker of prostate cancer. ETHICS AND DISSEMINATION: This study has been approved by the Yorkshire and The Humber-Bradford Leeds Research Ethics Committee (Reference: 21/YH/0305, IRAS: 297060, January 2022). The results will be presented in national and international conferences, published in peer-reviewed journals and will be communicated to relevant stakeholders. A plain English report will be shared with the study participants, patients' organisations and media. TRIAL REGISTRATION NUMBER: ISRCTN 12238218 (Amy Ackroyd NIHR CPMS Team).

Diffusion-weighted MRI in Advanced Epithelial Ovarian Cancer: Apparent Diffusion Coefficient as a Response Marker.

Background Treatment of advanced epithelial ovarian cancer results in a relapse rate of 75%. Early markers of response would enable optimization of management and improved outcome in both primary and recurrent disease. Purpose To assess the apparent diffusion coefficient (ADC), derived from diffusion-weighted MRI, as an indicator of response, progression-free survival (PFS), and overall survival. Materials and Methods This prospective multicenter trial (from 2012-2016) recruited participants with stage III or IV ovarian, primary peritoneal, or fallopian tube cancer (newly diagnosed, cohort one; relapsed, cohort two) scheduled for platinum-based chemotherapy, with interval debulking surgery in cohort one. Cohort one underwent two baseline MRI examinations separated by 0-7 days to assess ADC repeatability; an additional MRI was performed after three treatment cycles. Cohort two underwent imaging at baseline and after one and three treatment cycles. ADC changes in responders and nonresponders were compared (Wilcoxon rank sum tests). PFS and overall survival were assessed by using a multivariable Cox model. Results A total of 125 participants (median age, 63.3 years [interquartile range, 57.0-70.7 years]; 125 women; cohort one, n = 47; cohort two, n = 78) were included. Baseline ADC (range, 77-258 × 10-5mm2s-1) was repeatable (upper and lower 95% limits of agreement of 12 × 10-5mm2s-1 [95% confidence interval {CI}: 6 × 10-5mm2s-1 to 18 × 10-5mm2s-1] and -15 × 10-5mm2s-1 [95% CI: -21 × 10-5mm2s-1 to -9 × 10-5mm2s-1]). ADC increased in 47% of cohort two after one treatment cycle, and in 58% and 53% of cohorts one and two, respectively, after three cycles. Percentage change from baseline differed between responders and nonresponders after three cycles (16.6% vs 3.9%; P = .02 [biochemical response definition]; 19.0% vs 6.2%; P = .04 [radiologic definition]). ADC increase after one cycle was associated with longer PFS in cohort two (adjusted hazard ratio, 0.86; 95% CI: 0.75, 0.98; P = .03). ADC change was not indicative of overall survival for either cohort. Conclusion After three cycles of platinum-based chemotherapy, apparent diffusion coefficient (ADC) changes are indicative of response. After one treatment cycle, increased ADC is indicative of improved progression-free survival in relapsed disease. Published under a CC BY 4.0 license. Online supplemental material is available for this article.

Primary Rectal Cancer: Repeatability of Global and Local-Regional MR Imaging Texture Features.

Purpose To assess the day-to-day repeatability of global and local-regional magnetic resonance (MR) imaging texture features derived from primary rectal cancer. Materials and Methods After ethical approval and patient informed consent were obtained, two pretreatment T2-weighted axial MR imaging studies performed prospectively with the same imaging unit on 2 consecutive days in 14 patients with rectal cancer (11 men [mean age, 61.7 years], three women [mean age, 70.0 years]) were analyzed to extract (a) global first-order statistical histogram and model-based fractal features reflecting the whole-tumor voxel intensity histogram distribution and repeating patterns, respectively, without spatial information and (b) local-regional second-order and high-order statistical texture features reflecting the intensity and spatial interrelationships between adjacent in-plane or multiplanar voxels or regions, respectively. Repeatability was assessed for 46 texture features, and mean difference, 95% limits of agreement, within-subject coefficient of variation (wCV), and repeatability coefficient (r) were recorded. Results Repeatability was better for global parameters than for most local-regional parameters. In particular, histogram mean, median, and entropy, fractal dimension mean and standard deviation, and second-order entropy, homogeneity, difference entropy, and inverse difference moment demonstrated good repeatability, with narrow limits of agreement and wCVs of 10% or lower. Repeatability was poorest for the following high-order gray-level run-length (GLRL) gray-level zone size matrix (GLZSM) and neighborhood gray-tone difference matrix (NGTDM) parameters: GLRL intensity variability, GLZSM short-zone emphasis, GLZSM intensity nonuniformity, GLZSM intensity variability, GLZSM size zone variability, and NGTDM complexity, demonstrating wider agreement limits and wCVs of 50% or greater. Conclusion MR imaging repeatability is better for global texture parameters than for local-regional texture parameters, indicating that global texture parameters should be sufficiently robust for clinical practice. Online supplemental material is available for this article.

Arterial input functions in dynamic contrast-enhanced magnetic resonance imaging: which model performs best when assessing breast cancer response?

OBJECTIVE: To evaluate the performance of six models of population arterial input function (AIF) in the setting of primary breast cancer and neoadjuvant chemotherapy (NAC). The ability to fit patient dynamic contrast-enhanced MRI (DCE-MRI) data, provide physiological plausible data and detect pathological response was assessed. METHODS: Quantitative DCE-MRI parameters were calculated for 27 patients at baseline and after 2 cycles of NAC for 6 AIFs. Pathological complete response detection was compared with change in these parameters from a reproduction cohort of 12 patients using the Bland-Altman approach and receiver-operating characteristic analysis. RESULTS: There were fewer fit failures pre-NAC for all models, with the modified Fritz-Hansen having the fewest pre-NAC (3.6%) and post-NAC (18.8%), contrasting with the femoral artery AIF (19.4% and 43.3%, respectively). Median transfer constant values were greatest for the Weinmann function and also showed greatest reductions with treatment (-68%). Reproducibility (r) was the lowest for the Weinmann function (r = -49.7%), with other AIFs ranging from r = -27.8 to -39.2%. CONCLUSION: Using the best performing AIF is essential to maximize the utility of quantitative DCE-MRI parameters in predicting response to NAC treatment. Applying our criteria, the modified Fritz-Hansen and cosine bolus approximated Parker AIF models performed best. The Fritz-Hansen and biexponential approximated Parker AIFs performed less well, and the Weinmann and femoral artery AIFs are not recommended. ADVANCES IN KNOWLEDGE: We demonstrate that using the most appropriate AIF can aid successful prediction of response to NAC in breast cancer.

Phase I study of nintedanib incorporating dynamic contrast-enhanced magnetic resonance imaging in patients with advanced solid tumors.

BACKGROUND: This open-label phase I dose-escalation study investigated the safety, efficacy, pharmacokinetics (PK), and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) effects of the oral angiokinase inhibitor nintedanib in patients with advanced solid tumors. METHODS: Nintedanib was administered once daily continuously, starting at 100 mg and later amended to allow evaluation of 250 mg b.i.d. The primary endpoint was maximum tolerated dose (MTD). DCE-MRI studies were performed at baseline and on days 2 and 28. RESULTS: Fifty-one patients received nintedanib 100-450 mg once daily (n = 40) or 250 mg b.i.d. (n = 11). Asymptomatic reversible liver enzyme elevations (grade 3) were dose limiting in 2 of 5 patients at 450 mg once daily. At 250 mg b.i.d., 2 of 11 patients experienced dose-limiting toxicity (grade 3 liver enzyme elevation and gastrointestinal symptoms). Common toxicities included fatigue, diarrhea, nausea, vomiting, and abdominal pain (mainly grade ≤2). Among 45 patients, 22 (49%) achieved stable disease; 7 remained on treatment for >6 months. DCE-MRI of target lesions revealed effects in some patients at 200 and ≥400 mg once daily. CONCLUSION: Nintedanib is well tolerated by patients with advanced solid malignancies, with MTD defined as 250 mg b.i.d., and can induce changes in DCE-MRI. Disease stabilization >6 months was observed in 7 of 51 patients.

Assessing response in breast cancer with dynamic contrast-enhanced magnetic resonance imaging: are signal intensity-time curves adequate?

Quantitative DCE-MRI parameters including K(trans) (transfer constant min(-1)) can predict both response and outcome in breast cancer patients treated with neoadjuvant chemotherapy (NAC). Quantitative methods are time-consuming to calculate, requiring expensive software and interpretive expertise. For diagnostic purposes, signal intensity-time curves (SITCs) are used for tissue characterisation. In this study, we compare the ability of NAC-related changes in SITCs with K(trans) to predict response and outcomes. 73 women with primary breast cancer underwent DCE-MRI studies before and after two cycles of NAC. Patients received anthracycline and/or docetaxel-based chemotherapy. At completion of NAC, patients had local treatment with surgery & radiotherapy and further systemic treatments. SITCs for paired DCE-MRI studies were visually scored using a five-curve type classification schema encompassing wash-in and wash-out phases and correlated with K(trans) values and to the endpoints of pathological response, OS and DFS. 58 paired patients studies were evaluable. The median size by MRI measurement for 52 tumours was 38 mm (range 17-86 mm) at baseline and 26 mm (range 10-85 mm) after two cycles of NAC. Median baseline K(trans) (min(-1)) was 0.214 (range 0.085-0.469), and post-two cycles of NAC was 0.128 (range 0.013-0.603). SITC shapes were significantly related to K(trans) values both before (χ (2) = 43.3, P = 0.000) and after two cycles of NAC (χ (2) = 60.5, P = 0.000). Changes in curve shapes were significantly related to changes in K(trans) (χ (2) = 53.5, P = 0.000). Changes in curve shape were significantly correlated with clinical (P = 0.005) and pathological response (P = 0.005). Reductions in curve shape of ≥1 point were significant for overall improved survival using Kaplan-Meier analysis with a 5-year OS of 80.9 versus 68.6 % (P = 0.048). SITCs require no special software to generate and provide a useful method of assessing the effectiveness of NAC for primary breast cancer.

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/m(2) 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/m(2) 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.

Diffusion tensor imaging of the anal canal at 3 tesla: feasibility and reproducibility of anisotropy measures.

PURPOSE: To assess the feasibility and reproducibility of 3-tesla diffusion tensor imaging (DTI) of the anal canal. MATERIALS AND METHODS: DTI was performed in 25 men with no clinical history of anal canal disease undergoing MRI for prostate cancer. Analysis of fractional anisotropy (FA), relative anisotropy (RA), and apparent diffusion coefficient (ADC) were determined for the epithelial/subepithelial layer, internal sphincter, external sphincter, and puborectalis. The directionality of diffusion was recorded from color-coded tractography maps. Obturator internus and gluteus maximus served as reference muscles. Mean (SD) of values for FA, RA, and ADC were compared using analysis of variance. Intra and inter-rater agreement and test reproducibility (n = 5) was assessed by Bland-Altman statistics. RESULTS: Mean (SD) for the epithelial/subepithelial layer, internal, external sphincter, and puborectalis were as follows: FA: 0.283 (0.099); 0.337 (0.049); 0.415 (0.072); and 0.407 (0.062), respectively. RA: 0.241 (0.094); 0.292 (0.050); 0.371 (0.083); 0.361 (0.067), respectively; and ADC: 1.49 (0.23); 1.59 (0.19); 1.51 (0.28); and 1.54 (0.29) × 10(-3) mm(2) /s, respectively. Good overall intra and inter-rater agreement and test-retest reproducibility was noted (coefficient of variation of 4.8-19.4% and 5.9-12.9%, respectively). CONCLUSION: Anisotropy is evident in the anal canal with good inter-rater agreement and test reproducibility.

Assessing early therapeutic response to bevacizumab in primary breast cancer using magnetic resonance imaging and gene expression profiles.

Antiangiogenic therapy is a promising approach for the treatment of breast cancer. In practice, however, only a subset of patients who receive antiangiogenic drugs demonstrate a significant response. A key challenge, therefore, is to discover biomarkers that are predictive of response to antiangiogenic therapy. To address this issue, we have designed a window-of-opportunity study in which bevacizumab is administered as a short-term first-line treatment to primary breast cancer patients. Central to our approach is the use of a detailed pharmacodynamic assessment, consisting of pre- and post-bevacizumab multi-parametric magnetic resonance imaging scans and core biopsies for exon array gene expression analysis. Here, we illustrate three intrinsic patterns of response to bevacizumab and discuss the molecular mechanisms that may underpin each. Our results illustrate how the combination of dynamic imaging data and gene expression profiles can guide the development of biomarkers for predicting response to antiangiogenic therapy.

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.

Vascular characterisation of triple negative breast carcinomas using dynamic MRI.

OBJECTIVES: Triple-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. METHODS: Patients 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 (K(trans)), outflow rate constant (k(ep)), leakage space (v(e)), area under the gadolinium curve (IAUGC(60) ), relative blood volume (rBV) and flow (rBF), and Mean Transit Time (MTT) were compared across receptor status and with known prognostic variables. RESULTS: Thirty seven patients were assessable in total (16 ER-/PR-/HER2-, 21 ER+/PR+/HER2-). Lower v(e) (p = 0.001), shorter MTT (p = 0.007) and higher k(ep) values (p = 0.044) were observed in TNBC. v(e) was lower across all T stages, node-negative (p = 0.004) and low-grade TNBC (p = 0.037). v(e) was the best predictor of triple negativity (ROC AUC 0.80). CONCLUSIONS: TNBC 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.

Antivascular effects of neoadjuvant androgen deprivation for prostate cancer: an in vivo human study using susceptibility and relaxivity dynamic MRI.

PURPOSE: The antivascular effects of androgen deprivation have been investigated in animal models; however, there has been minimal investigation in human prostate cancer. This study tested the hypothesis that androgen deprivation causes significant reductions in human prostate tumor blood flow and the induction of hypoxia at a magnitude and in a time scale relevant to the neoadjuvant setting before radiotherapy. METHODS AND MATERIALS: Twenty patients were examined, each with five multi-parameter magnetic resonance imaging scans: two scans before the commencement of androgen suppression, one scan after 1 month of hormone treatment, and two further scans after 3 months of therapy. Quantitative parametric maps of the prostate informing on relative blood flow (rBF), relative blood volume (rBV), vascular permeability (transfer constant [K(trans)]), leakage space (v(e)) and blood oxygenation (intrinsic relaxivity [R(2)∗]) were calculated. RESULTS: Tumor blood volume and blood flow decreased by 83% and 79%, respectively, in the first month (p < 0.0001), with 74% of patients showing significant changes. The proportion of individual patients who achieved significant changes in T1 kinetic parameter values after 3 months of androgen deprivation for tumor measurements was 68% for K(trans) and 53% for v(e) By 3 months, significant increases in R(2)∗ had occurred in prostate tumor, with a rise of 41.1% (p < 0.0001). CONCLUSIONS: Androgen deprivation induces profound vascular collapse within 1 month of starting treatment. Increased R(2)∗ in regions of prostate cancer and a decrease in blood volume suggest a reduction in tumor oxygenation.

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.

Reproducibility and correlation between quantitative and semiquantitative dynamic and intrinsic susceptibility-weighted MRI parameters in the benign and malignant human prostate.

PURPOSE: To assess the reproducibility of relaxivity- and susceptibility-based dynamic contrast-enhanced magnetic resonance imaging (MRI) in the benign and malignant prostate gland and to correlate the kinetic parameters obtained. MATERIALS AND METHODS: Twenty patients with prostate cancer underwent paired scans before and after androgen deprivation therapy. Quantitative parametric maps for T(1)- and T(2)*-weighted parameters were calculated (K(trans), k(ep),v(e), IAUC(60), rBV, rBF, and R(2)*). The reproducibility of and correlation between each parameter were determined using standard methods at both timepoints. RESULTS: T(1)-derived parameters are more reproducible than T(2)*-weighted measures, both becoming more variable following androgen deprivation (variance coefficients for prostate K(trans) and rBF increased from 13.9%-15.8% and 42.5%-90.8%, respectively). Tumor R(2)* reproducibility improved after androgen ablation (23.3%-11.8%). IAUC(60) correlated strongly with K(trans), v(e), and k(ep) (all P < 0.001). R(2)* did not correlate with other parameters. CONCLUSION: This study is the first to document the variability and repeatability of T(1)- and T(2)*-weighted dynamic MRI and intrinsic susceptibility-weighted MRI for the various regions of the human prostate gland before and after androgen deprivation. These data provide a valuable source of reference for groups that plan to use dynamic contrast-enhanced MRI or intrinsic susceptibility-weighted MRI for the assessment of treatment response in the benign or malignant prostate.

Reproducibility and changes in the apparent diffusion coefficients of solid tumours treated with combretastatin A4 phosphate and bevacizumab in a two-centre phase I clinical trial.

The purpose was to determine the reproducibility of apparent diffusion coefficient (ADC) measurements in a two-centre phase I clinical trial; and to track ADC changes in response to the sequential administration of the vascular disrupting agent, combretastatin A4 phosphate (CA4P), and the anti-angiogenic drug, bevacizumab. Sixteen patients with solid tumours received CA4P and bevacizumab treatment. Echo-planar diffusion-weighted MRI was performed using six b values (b = 0-750 s/mm(2)) before (x2), and at 3 and 72 h after a first dose of CA4P. Bevacizumab was given 4 h after a second dose of CA4P, and imaging performed 3 h post CA4P and 72 h after bevacizumab treatment. The coefficient of repeatability (r) of ADC total (all b values), ADC high (b = 100-750) and ADC low (b = 0-100) was calculated by Bland-Altman analysis. The ADC total and ADC high showed good measurement reproducibility (r% = 13.3, 14.1). There was poor reproducibility of the perfusion-sensitive ADC low (r% = 62.5). Significant increases in the median ADC total and ADC high occurred at 3 h after the second dose of CA4P (p < 0.05). ADC measurements were highly reproducible in a two-centre clinical trial setting and appear promising for evaluating the effects of drugs that target tumour vasculature.

A phase I trial of radioimmunotherapy with 131I-A5B7 anti-CEA antibody in combination with combretastatin-A4-phosphate in advanced gastrointestinal carcinomas.

PURPOSE: In preclinical models, radioimmunotherapy with (131)I-A5B7 anti-carcinoembryonic antigen (CEA) antibody ((131)I-A5B7) combined with the vascular disruptive agent combretastatin-A4-phosphate (CA4P) produced cures unlike either agent alone. We conducted a phase I trial determining the dose-limiting toxicity (DLT), maximum tolerated dose, efficacy, and mechanism of this combination in patients with gastrointestinal adenocarcinomas. EXPERIMENTAL DESIGN: Patients had CEA of 10 to 1,000 microg/L, QTc < or =450 ms, no cardiac arrhythmia/ischaemia, and adequate hematology/biochemistry. Tumor was suitable for blood flow analysis by dynamic contrast enhanced-magnetic resonance imaging (MRI). The starting dose was 1,800 MBq/m(2) of (131)I-A5B7 on day 1 and 45 mg/m(2) CA4P given 48 and 72 hours post-(131)I-A5B7, then weekly for up to seven weeks. RESULTS: Twelve patients were treated, with mean age of 63 years (range, 32-77). Two of six patients at the first dose level had DLTs (grade 4 neutropenia). The dose was reduced to 1,600 MBq/m(2), and CA4P escalated to 54 mg/m(2). Again, two of six patients had DLTs (neutropenia). Of ten assessable patients, three had stable disease and seven had progressive disease. Single-photon emission computed tomography confirmed tumor antibody uptake in all 10 patients. DCE-MRI confirmed falls in kinetic parameters (K(trans)/IAUGC(60)) in 9 of 12 patients. The change of both pharmacokinetic parameters reached a level expected to produce efficacy in one patient who had a minor response on computed tomography and a reduced serum tumor marker level. CONCLUSIONS: This is believed to be the first trial reporting the combination of radioimmunotherapy and vascular disruptive agent; each component was shown to function, and myelosuppression was dose-limiting. Optimal dose and timing of CA4P, and moderate improvements in the performance of radioimmunotherapy seem necessary for efficacy.

A Bayesian hierarchical model for the analysis of a longitudinal dynamic contrast-enhanced MRI oncology study.

Imaging in clinical oncology trials provides a wealth of information that contributes to the drug development process, especially in early phase studies. This article focuses on kinetic modeling in DCE-MRI, inspired by mixed-effects models that are frequently used in the analysis of clinical trials. Instead of summarizing each scanning session as a single kinetic parameter--such as median k(trans) across all voxels in the tumor ROI-we propose to analyze all voxel time courses from all scans and across all subjects simultaneously in a single model. The kinetic parameters from the usual nonlinear regression model are decomposed into unique components associated with factors from the longitudinal study; e.g., treatment, patient, and voxel effects. A Bayesian hierarchical model provides the framework to construct a data model, a parameter model, as well as prior distributions. The posterior distribution of the kinetic parameters is estimated using Markov chain Monte Carlo (MCMC) methods. Hypothesis testing at the study level for an overall treatment effect is straightforward and the patient- and voxel-level parameters capture random effects that provide additional information at various levels of resolution to allow a thorough evaluation of the clinical trial. The proposed method is validated with a breast cancer study, where the subjects were imaged before and after two cycles of chemotherapy, demonstrating the clinical potential of this method to longitudinal oncology studies.

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 (K(trans), k(ep), v(e), 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 K(trans), k(ep), MaxGd, rBV, and rBF were significantly correlated with both final clinical and pathologic response (P < 0.01). Change in K(trans) 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.

Hypoxia in prostate cancer: correlation of BOLD-MRI with pimonidazole immunohistochemistry-initial observations.

PURPOSE: To investigate the ability of blood oxygen level-dependent (BOLD) MRI to depict clinically significant prostate tumor hypoxia. METHODS AND MATERIALS: Thirty-three patients with prostate carcinoma undergoing radical prostatectomy were studied preoperatively, using gradient echo sequences without and with contrast medium enhancement, to map relative tissue oxygenation according to relaxivity rates and relative blood volume (rBV). Pimonidazole was administered preoperatively, and whole-mount sections of selected tumor-bearing slices were stained for pimonidazole fixation and tumor and nontumor localization. Histologic and imaging parameters were independently mapped onto patient prostate outlines. Using 5-mm grids, 861 nontumor grid locations were compared with 237 tumor grids (with >50% tumor per location) using contingency table analysis with respect to the ability of imaging to predict pimonidazole staining. RESULTS: Twenty patients completed the imaging and histologic protocols. Pimonidazole staining was found in 33% of nontumor and in 70% of tumor grids. The sensitivity of the MR relaxivity parameter R(2)* in depicting tumor hypoxia was high (88%), improving with the addition of low rBV information (95%) without changing specificity (36% and 29%, respectively). High R(2)* increased the positive predictive value for hypoxia by 6% (70% to 76%); conversely, low R(2)* decreased the likelihood of hypoxia being present by 26% (70% to 44%) and by 41% (71% to 30%) when combined with rBV information. CONCLUSION: R(2)* maps from BOLD-MRI have high sensitivity but low specificity for defining intraprostatic tumor hypoxia. This together with the negative predictive value of 70% when combined with blood volume information makes BOLD-MRI a potential noninvasive technique for mapping prostatic tumor hypoxia.