Enhancement Fraction Research Articles

Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study

ObjectiveRegorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection.DesignPatients with RAS mutant...

Magnetic resonance Imaging (MRI), liquid biopsies, and patient derived organoids (PDOs) as biomarkers of response to regorafenib (REG) in treatment-refractory metastatic colorectal cancer (mCRC) patients (pts).

613 Background: REG demonstrated efficacy in pre-treated mCRC pts. Lack of predictive biomarkers, potential toxicities and cost/effectiveness concerns highlight the unmet need for better patient selection. Methods: RAS mutant mCRC pts with biopsiable metastases were enrolled in this phase II trial. Tissue biopsies (6-12 cores) were obtained at baseline (BL), after 2 months if stable disease (SD) and at disease progression (PD). Dynamic contrast enhanced (DCE) MRI was acquired pre and at day 15 post-treatment. Median values of volume transfer constant (Ktrans) and enhancing fraction (EF) [K-trans*EF/100] were generated. Circulating tumour (ct)DNA was collected monthly until PD and tested for clonal RAS mutations by digital droplet PCR. PDOs derived from responders and non-responders pts were implanted orthotopically in the liver of mice and treated with REG for 5 days. Changes in tumour and fractional blood volume (fBV) were monitored by oxygen-enhanced MRI. Results: mCRC pts (n = 27) with paired MRI scans were analysed; a single target lesion per pt was chosen (25 liver and 2 pelvic metastases). Median K-trans*EF/100 product decrease was 58.2%. In the 23 analysable pts (4 received < 1 cycle of treatment due to toxicities), > 70% drop in K-trans*EF/100 (8/23) was associated with higher disease control rate (6/6 vs. 0/6, p = 0.048) measured by RECIST 1.1 at 2 months, improved progression free survival (PFS) [HR = 0.24 (0.07-0.86), p = 0.03], and 4-month PFS (58.3% VS 21.2%). Sequential tissue biopsies analysis confirmed reduction in CD31 in pts with K-trans*EF/100 drop. RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS [HR = 0.25 (0.08 - 0.83), p = 0.02] independently of K-trans*EF/100 drop. PDOs xeno-transplants treated with REG compared to controls had significant lower tumour fBV (4.5 VS 10.6, p = 0.03) and lower microvascular density measured by CD31 staining (4.3 VS 8.9, p = 0.02). Conclusions: Combining DCE MRI and ctDNA predicts depth and duration of anti-angiogenic response to REG monotherapy and may improve pt selection with potential health/economic implications. Clinical trial information: 201400357951.

Multi-parametric MRI in the early prediction of response to neo-adjuvant chemotherapy in breast cancer: Value of non-modelled parameters

ObjectiveTo prospectively evaluate individual functional MRI metrics for the early prediction of pathological complete response (pCR) to neo-adjuvant chemotherapy (NAC) in breast cancer. Materials and methodsThirty-two women (median age 52 years; range 32–71 years) with biopsy proven breast cancer due to receive neo-adjuvant anthracycline and/or taxane-based chemotherapy were prospectively recruited following local research ethics committee approval and written informed consent. Breast MRI was performed prior to and after two cycles of NAC and pCR was assessed after surgery. The enhancement fraction (EF), tumour volume, initial area under the gadolinium curve (IAUGC), pharmacokinetic parameters (Ktrans, kep and ve), the apparent diffusion coefficient (ADC) and R2* values, along with the percentage change in these parameters after two cycles were evaluated according to pCR status using an independent samples t-test. The area under the receiver operating characteristics curve (AUC) was calculated for each parameter. Linear discriminant analysis (LDA) determined the most important parameter in predicting pCR. ResultsA reduction in the EF (−41%±38%) and tumour volume (−80%±25%) after 2 cycles of NAC were significantly greater in those achieving pCR (p=0.025, p=0.011 respectively). A reduction in the EF of 7% after 2 cycles of NAC identified those more likely to achieve pCR (AUC 0.76). AUC changes in other parameters were tumour volume (0.77), IAUGC (0.64), Ktrans (0.60), kep (0.68), ve (0.58), ADC (0.69) and R2* (0.41). ConclusionIn a multi-parametric MRI model, the decrease in a non-model based vascular parameter the enhancement fraction as well as the tumour volume are the most important early predictors of pCR in breast cancer.

Dynamic oxygen-enhanced magnetic resonance imaging of the lung in asthma—Initial experience

ObjectivesTo prospectively estimate the feasibility and reproducibility of dynamic oxygen-enhanced magnetic resonance imaging (OE-MRI) in the assessment of regional oxygen delivery, uptake and washout in asthmatic lungs. Materials and methodsThe study was approved by the National Research Ethics Committee and written informed consent was obtained. Dynamic OE-MRI was performed twice at one month apart on four mild asthmatic patients (23±5 years old, FEV1=96±3% of predicted value) and six severe asthmatic patients (41±12 years old, FEV1=60±14% of predicted value) on a 1.5T MR scanner using a two-dimensional T1-weighted inversion-recovery turbo spin echo sequence. The enhancing fraction (EF), the maximal change in the partial pressure of oxygen in lung tissue (ΔPO2max_l) and arterial blood of the aorta (ΔPO2max_a), and the oxygen wash-in (τup_l, τup_a) and wash-out (τdown_l, τdown_a) time constants were extracted and compared between groups using the independent-samples t-test (two-tailed). Correlations between imaging readouts and clinical measurements were assessed by Pearson's correlation analysis. Bland–Altman analysis was used to estimate the levels of agreement between the repeat scans and the intra-observer agreement in the MR imaging readouts. ResultsThe severe asthmatic group had significantly smaller EF (70±16%) and median ΔPO2max_l (156±52mmHg) and significantly larger interquartile range of τup_l (0.84±0.26min) than the mild asthmatic group (95±3%, P=0.014; 281±40mmHg, P=0.004; 0.20±0.07min, P=0.001, respectively). EF, median ΔPO2max_l and τdown_l and the interquartile range of τup_l and τdown_l were significantly correlated with age and pulmonary function test parameters (r=−0.734 to −0.927, 0.676–0.905; P=0.001–0.045). Median ΔPO2max_l was significantly correlated with ΔPO2max_a (r=0.745, P=0.013). Imaging readouts showed good one-month reproducibility and good intra-observer agreement (mean bias between repeated scans and between two observations did not significantly deviate from zero). ConclusionsDynamic OE-MRI is feasible in asthma and sensitive to the severity of disease. The technique provides indices related to regional oxygen delivery, uptake and washout that show good one month reproducibility and intra-observer agreement.

DCE-MRI biomarkers of tumour heterogeneity predict CRC liver metastasis shrinkage following bevacizumab and FOLFOX-6.

Background:There is limited evidence that imaging biomarkers can predict subsequent response to therapy. Such prognostic and/or predictive biomarkers would facilitate development of personalised medicine. We hypothesised that pre-treatment measurement of the heterogeneity of tumour vascular enhancement could predict clinical outcome following combination anti-angiogenic and cytotoxic chemotherapy in colorectal cancer (CRC) liver metastases.Methods:Ten patients with 26 CRC liver metastases had two dynamic contrast-enhanced MRI (DCE-MRI) examinations before starting first-line bevacizumab and FOLFOX-6. Pre-treatment biomarkers of tumour microvasculature were computed and a regression analysis was performed against the post-treatment change in tumour volume after five cycles of therapy. The ability of the resulting linear model to predict tumour shrinkage was evaluated using leave-one-out validation. Robustness to inter-visit variation was investigated using data from a second baseline scan.Results:In all, 86% of the variance in post-treatment tumour shrinkage was explained by the median extravascular extracellular volume (ve), tumour enhancing fraction (EF), and microvascular uniformity (assessed with the fractal measure box dimension, d0) (R2=0.86, P<0.00005). Other variables, including baseline volume were not statistically significant. Median prediction error was 12%. Equivalent results were obtained from the second scan.Conclusion:Traditional image analyses may over-simplify tumour biology. Measuring microvascular heterogeneity may yield important prognostic and/or predictive biomarkers.

A two-part Phase II study of cediranib in patients with advanced solid tumours: the effect of food on single-dose pharmacokinetics and an evaluation of safety, efficacy and imaging pharmacodynamics

Cediranib (RECENTIN™) is an oral, highly potent VEGF inhibitor. This study evaluated the effect of food on the pharmacokinetics of cediranib and compared the administration of continual cediranib via two dosing strategies using this as a platform to investigate pharmacodynamic imaging biomarkers. Sixty patients were randomised to receive two single doses of cediranib in either fed/fasted or fasted/fed state (Part A). In continual dosage phase (Part B), patients were randomised to a fixed-dose or dose-escalation arm. Exploratory pharmacodynamic assessments were performed using DCE-MRI and CT enhancing fraction (EnF). In part A, plasma AUC and C (max) of cediranib were lower in the presence of food by a mean of 24 and 33%, respectively (94% CI: AUC, 12-34% and C (max), 20-43%), indicating food reduces cediranib plasma exposure. In part B, cediranib 30mg/day appeared to be the most sustainable for chronic dosing. Continuous cediranib therapy was associated with sustained antivascular effects up to 16weeks, with significant reductions in DCE-MRI parameters and CT EnF. It is recommended that cediranib be administered at least 1h before or 2h after food. Evidence of antitumour activity was observed, with significant sustained effects upon imaging vascular parameters.

Tumour enhancing fraction (EnF) in glioma: relationship to tumour grade

The aim of this research was to determine whether the proportion of a tumour that enhances (enhancing fraction, EnF) and changes in EnF with enhancement threshold differ between low and high grade glioma. Forty-four patients (45 gliomas comprising 16 grade II, 5 grade III and 24 grade IV) were studied. Imaging included pre- and post-contrast-enhanced T(1)-weighted sequences and T(1)-weighted DCE-MRI. Thresholded enhancement maps were generated for each tumour by using a range of values of the initial area under the contrast concentration curve (IAUC). A plot of EnF versus threshold value was generated. We examined the relationship between tumour grade and enhancement metrics including: EnF (threshold IAUC > 0 mMol s), EnF (threshold IAUC > 2.5 mMol s), initial slope of the EnF/threshold curve (partial differentialEnF), IAUC, and two previously described signal-intensity-based metrics. EnF, defined as the proportion of tumour showing any enhancement (threshold IAUC > 0 mMol s), showed no difference between low and high grade glioma. All other measures demonstrated significant differences between grade II and IV, and low (grade II) and high grade (grades III/ IV) gliomas (p < 0.01). Two measures, partial differentialEnF and Pronin's measure of enhancement, showed differences between grade III and IV (p < 0.05). No measure separated grade II from III. Metrics which describe the enhancing fraction and its variation with enhancement threshold partial differentialEnF show considerably different behaviour in low and high grade tumours. These observations suggest that these metrics may provide important biological information concerning tumour biology and therapeutic responses and encourage further research to characterise and validate these novel biomarkers.