Pretreatment Dynamic Contrast-enhanced MRI Research Articles

Hepatic arterial infusion for unresectable intrahepatic cholangiocarcinoma: An update on survival from two prospective clinical trials.

4116 Background: Patients with unresectable intrahepatic cholangiocarcinoma (IHC) experience poor survival. This study summarizes the long-term outcome of two previously reported clinical trials using hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone (Dex) (with or without bevacizumab (Bev)) in advanced IHC. Methods: Prospectively collected clinicopathologic and survival data were retrospectively reviewed. Disease response was based on RECIST. All patients underwent pre-treatment dynamic contrast enhanced MRI (DCE-MRI), and tumor perfusion data were correlated with outcome. Results: Forty-four patients were analyzed (FUDR=26, FUDR/Bev=18). At a median follow-up of 30 months, 41 patients had died of disease and 3 were alive. Partial response was observed in 48% of patients, and another 50% had stable disease. Three patients underwent resection after HAI and 84% received additional HAI after removal from the study. Median survival was similar in both trials (FUDR=29 months vs. FUDR/Bev=28.5 months p=0.96). Ten patients (23%) survived ≥3 years including 5 (11%) ≥ 5 years. Tumor perfusion, as measured on pre-treatment DCE-MRI (area under the gadolinium concentration curve (AUC180)), was significantly higher in ≥3-year survivors, and was the only factor that distinguished this group from <3-year survivors (mean AUC180 48.9mM.s vs 32.3mM.s, respectively; p=0.003). Time to liver progression was longer in ≥3-year survivors (19.8 months vs 11.2 months, respectively; p=0.02). Conclusions: HAI chemotherapy can result in prolonged survival in unresectable IHC. Pre-treatment DCE-MRI may predict response and survival. [Table: see text]

Pretreatment Diffusion-Weighted and Dynamic Contrast-Enhanced MRI for Prediction of Local Treatment Response in Squamous Cell Carcinomas of the Head and Neck

The objective of our study was to predict response to chemoradiation therapy in patients with head and neck squamous cell carcinoma (HNSCC) by combined use of diffusion-weighted imaging (DWI) and high-spatial-resolution, high-temporal-resolution dynamic contrast-enhanced MRI (DCE-MRI) parameters from primary tumors and metastatic nodes. Thirty-two patients underwent pretreatment DWI and DCE-MRI using a modified radial imaging sequence. Postprocessing of data included motion-correction algorithms to reduce motion artifacts. The median apparent diffusion coefficient (ADC), volume transfer constant (K(trans)), extracellular extravascular volume fraction (v(e)), and plasma volume fraction (v(p)) were computed from primary tumors and nodal masses. The quality of the DCE-MRI maps was estimated using a threshold median chi-square value of 0.10 or less. Multivariate logistic regression and receiver operating characteristic curve analyses were used to determine the best model to discriminate responders from nonresponders. Acceptable χ(2) values were observed from 84% of primary tumors and 100% of nodal masses. Five patients with unsatisfactory DCE-MRI data were excluded and DCE-MRI data for three patients who died of unrelated causes were censored from analysis. The median follow-up for the remaining patients (n = 24) was 23.72 months. When ADC and DCE-MRI parameters (K(trans), v(e), v(p)) from both primary tumors and nodal masses were incorporated into multivariate logistic regression analyses, a considerably higher discriminative accuracy (area under the curve [AUC] = 0.85) with a sensitivity of 81.3% and specificity of 75% was observed in differentiating responders (n = 16) from nonresponders (n = 8). The combined use of DWI and DCE-MRI parameters from both primary tumors and nodal masses may aid in prediction of response to chemoradiation therapy in patients with HNSCC.

Prospective Trial of Synchronous Bevacizumab, Erlotinib, and Concurrent Chemoradiation in Locally Advanced Head and Neck Cancer

We assessed the safety and efficacy of synchronous VEGF and epidermal growth factor receptor (EGFR) blockade with concurrent chemoradiation (CRT) in locally advanced head and neck cancer (HNC). Newly diagnosed patients with stage III/IV HNC received a 2-week lead-in of bevacizumab and/or erlotinib, followed by both agents with concurrent cisplatin and twice daily radiotherapy. Safety was assessed using Common Toxicity Criteria version 3.0. The primary efficacy endpoint was clinical complete response (CR) rate after CRT. Twenty-nine patients enrolled on study, with 27 completing therapy. Common grade III toxicities were mucositis (n = 14), dysphagia (n = 8), dehydration (n = 7), osteoradionecrosis (n = 3), and soft tissue necrosis (n = 2). Feeding tube placement was required in 79% but no patient remained dependent at 12-month posttreatment. Clinical CR after CRT was 96% [95% confidence interval (CI), 82%-100%]. Median follow-up was 46 months in survivors, with 3-year locoregional control and distant metastasis-free survival rates of 85% and 93%. Three-year estimated progression-free survival, disease-specific survival, and overall survival rates were 82%, 89%, and 86%, respectively. Dynamic contrast enhanced MRI (DCE-MRI) analysis showed that patients who had failed had lower baseline pretreatment median K(trans) values, with subsequent increases after lead-in therapy and 1 week of CRT. Patients who did not fail had higher median K(trans) values that decreased during therapy. Dual VEGF/EGFR inhibition can be integrated with CRT in locally advanced HNC, with efficacy that compares favorably with historical controls albeit with an increased risk of osteoradionecrosis. Pretreatment and early DCE-MRI may prospectively identify patients at high risk of failure.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging as a Predictor of Outcome in Head-and-Neck Squamous Cell Carcinoma Patients With Nodal Metastases

Dynamic contrast-enhanced MRI (DCE-MRI) can provide information regarding tumor perfusion and permeability and has shown prognostic value in certain tumors types. The goal of this study was to assess the prognostic value of pretreatment DCE-MRI in head and neck squamous cell carcinoma (HNSCC) patients with nodal disease undergoing chemoradiation therapy or surgery. Seventy-four patients with histologically proven squamous cell carcinoma and neck nodal metastases were eligible for the study. Pretreatment DCE-MRI was performed on a 1.5T MRI. Clinical follow-up was a minimum of 12 months. DCE-MRI data were analyzed using the Tofts model. DCE-MRI parameters were related to treatment outcome (progression-free survival [PFS] and overall survival [OS]). Patients were grouped as no evidence of disease (NED), alive with disease (AWD), dead with disease (DOD), or dead of other causes (DOC). Prognostic significance was assessed using the log-rank test for single variables and Cox proportional hazards regression for combinations of variables. At last clinical follow-up, for Stage III, all 12 patients were NED. For Stage IV, 43 patients were NED, 4 were AWD, 11 were DOD, and 4 were DOC. K(trans) is volume transfer constant. In a stepwise Cox regression, skewness of K(trans) (volume transfer constant) was the strongest predictor for Stage IV patients (PFS and OS: p <0.001). Our study shows that skewness of K(trans) was the strongest predictor of PFS and OS in Stage IV HNSCC patients with nodal disease. This study suggests an important role for pretreatment DCE-MRI parameter K(trans) as a predictor of outcome in these patients.

Heterogeneity in DCE-MRI parametric maps: a biomarker for treatment response?

This study aims to quantify the heterogeneity of tumour enhancement in dynamic contrast-enhanced MRI (DCE-MRI) using texture analysis methods. The suitability of the coherence and the fractal dimension to monitor tumour response was evaluated in 18 patients with limb sarcomas imaged by DCE-MRI pre- and post-treatment. According to the histopathology, tumours were classified into responders and non-responders. Pharmacokinetic (Ktrans) and heuristic model-based parametric maps (slope, max enhancement, AUC) were computed from the DCE-MRI data. A substantial correlation was found between the pharmacokinetic and heuristic model-based parametric maps: ρ = 0.56 for the slope, ρ = 0.44 for maximum enhancement, and ρ = 0.61 for AUC. From all four parametric maps, the enhancing fraction, and the heterogeneity features (i.e. coherence and fractal dimension) were determined. In terms of monitoring tumour response, using both pre- and post-treatment DCE-MRI, the enhancing fraction and the coherence showed significant differences between the response group and the non-response group (i.e. the highest sensitivity (91%) for Ktrans, and the highest specificity (83%) for max enhancement). In terms of treatment prediction, using solely the pre-treatment DCE-MRI, the enhancing fraction and coherence discriminated between responders and non-responders. For prediction, the highest sensitivity (91%) was shared by Ktrans, slope and max enhancement, and the highest specificity (71%) was achieved by Ktrans. On average, tumours that responded showed a high enhancing fraction and high coherence on the pre-treatment scan. These results suggest that specific heterogeneity features, computed from both pharmacokinetic and heuristic model-based parametric maps, show potential as a biomarker for monitoring tumour response.

Abstract 5245: Regional analysis of DCE MR images to unravel tumor growth and response heterogeneity in SW-620 human colon adenocarcinoma xenografts

Abstract Introduction: Dynamic Contrast-Enhanced (DCE) MRI, a clinically relevant technique used to assess response to anti-angiogenic therapies, relies on imaging of a T1 modifying contrast agent to characterize vascular response by the dynamics of tracer exchange between the vessels and the interstitial space. The parameter Ktrans is a measure of the tumor vascular permeability, vascular surface area and blood flow, and is normally assessed as mean over the entire tumor volume. Generally, decreasing tumor mean Ktrans occurs after effective vascular targeting. However, localized tumor growth based necrosis/under-perfusion can also lower Ktrans, leading to uncoupling of the endpoint from the effect. Techniques that can overcome confounding effects of heterogeneity may improve Ktrans sensitivity and correlation with outcome. We applied a thresholding technique to Ktrans data to analyze regional Ktrans variations in subcutaneous SW-620 tumors treated with the vascular targeted agent, bevacizumab or vehicle. Materials and Methods: Female nu/nu mice were implanted with SW-620 tumor fragments on Day 0. On Day 14, mice were distributed into groups with matching tumor burden. DCE-MRI images were acquired 24 hours before treatment (vehicle or bevacizumab; IP; 5mg/kg; Q3Dx4), and one week after treatment. The data were fitted to a Tofts-Kermode kinetic model to generate Ktrans over the entire tumor volume. Thresholds we determined by pooling all the Ktransvalues from the pre-treatment DCE MRI scans. The Ktrans values for each image were distributed into low, mid and high Ktrans fractions and the percentage of voxels in each fraction was calculated. Results: Bevacusimab resulted in moderate tumor growth inhibition (T/C = 43% on Day 22). Tumor mean Ktrans one week post-treatment start did not correlate with this effect, with Ktrans (T/C) = 131%. Analysis of location of voxels in the low, mid and high Ktrans fractions in the pre-treatment images showed that lower Ktrans values were generally confined to the tumor core, while higher Ktrans values were generally confined to the tumor periphery. These regions presumably related to under-perfused (core) and well perfused (periphery) tissue. A comparison of the high Ktrans volume fractions one week post-treatment (treated vs control) showed a correlation with the growth based treatment effect (high Ktrans volume fraction (T/C) = 44%). Ktrans thresholding may therefore provide a means to increasing sensitivity to treatment-based vascular inhibition. 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 5245.

MR quantification of abnormal stromal enhancement in the periphery of invasive breast tumors

636 Background: In dynamic contrast-enhanced MRI (DCEMRI), properties of tissue microvasculature and overall vascularity can be quantified using kinetics of contrast enhancement. It has been shown that areas with high signal enhancement ratio (SER) were significantly correlated with high tumor vascularity, and that mean SER in nearby non-cancerous breast stroma was significantly associated with disease free survival. No universally accepted methods exist to determine the optimal extent of histologically normal breast tissue to treat. Although a relationship between normal tissue SER and recurrence has been observed, the spatial relationship of enhancement within the non-cancerous stroma with respect to proximity of the tumor has not been shown. We hypothesized that abnormalities in vasculature exist within the histologically normal breast stroma that can be detected by measuring changes in enhancement intensity. Methods: We performed a secondary analysis of pre-treatment DCEMRI data from 27 invasive breast cancer patients. An automated, user-independent program was used to segment breast tissue from all other structures. A SER threshold was set to identify invasive tumor regions, and a tumor proximity map was generated giving the 3D distance of each normal breast tissue voxel to the nearest tumor voxel. A percent enhancement (PE) map was calculated for the normal stroma using the signal intensity change between the pre-contrast and post-contrast images. The proximity and PE maps were then combined to measure breast tissue enhancement at various distances from the tumor. Results: PE levels in normal breast tissue situated within 2 cm of the tumor region were significantly higher than at all more distant regions. Pairwise comparisons with Turkey's adjusted p-values indicated that the mean PE at 0 cm-1 cm is significantly higher than all other distant levels (p = &lt; 0.0001) and the mean PE at 1 cm-2 cm is significantly higher than 5 cm-6 cm (p = 0.006). Conclusions: Here, we show that the normal-appearing breast stroma within 0 cm to 2 cm of a primary tumor exhibits higher enhancement levels than stroma located far from the tumor. These results suggest that tissue surrounding the tumor region may contain tumor-related angiogenesis. These findings could help personalize surgery and radiation techniques. No significant financial relationships to disclose.

Average arterial input function for quantitative dynamic contrast enhanced magnetic resonance imaging of neck nodal metastases

BackgroundThe present study determines the feasibility of generating an average arterial input function (Avg-AIF) from a limited population of patients with neck nodal metastases to be used for pharmacokinetic modeling of dynamic contrast-enhanced MRI (DCE-MRI) data in clinical trials of larger populations.MethodsTwenty patients (mean age 50 years [range 27–77 years]) with neck nodal metastases underwent pretreatment DCE-MRI studies with a temporal resolution of 3.75 to 7.5 sec on a 1.5T clinical MRI scanner. Eleven individual AIFs (Ind-AIFs) met the criteria of expected enhancement pattern and were used to generate Avg-AIF. Tofts model was used to calculate pharmacokinetic DCE-MRI parameters. Bland-Altman plots and paired Student t-tests were used to describe significant differences between the pharmacokinetic parameters obtained from individual and average AIFs.ResultsInd-AIFs obtained from eleven patients were used to calculate the Avg-AIF. No overall significant difference (bias) was observed for the transfer constant (Ktrans) measured with Ind-AIFs compared to Avg-AIF (p = 0.20 for region-of-interest (ROI) analysis and p = 0.18 for histogram median analysis). Similarly, no overall significant difference was observed for interstitial fluid space volume fraction (ve) measured with Ind-AIFs compared to Avg-AIF (p = 0.48 for ROI analysis and p = 0.93 for histogram median analysis). However, the Bland-Altman plot suggests that as Ktrans increases, the Ind-AIF estimates tend to become proportionally higher than the Avg-AIF estimates.ConclusionWe found no statistically significant overall bias in Ktrans or ve estimates derived from Avg-AIF, generated from a limited population, as compared with Ind-AIFs.However, further study is needed to determine whether calibration is needed across the range of Ktrans. The Avg-AIF obtained from a limited population may be used for pharmacokinetic modeling of DCE-MRI data in larger population studies with neck nodal metastases. Further validation of the Avg-AIF approach with a larger population and in multiple regions is desirable.

Prognostic value of pre-treatment DCE-MRI parameters in predicting disease free and overall survival for breast cancer patients undergoing neoadjuvant chemotherapy

The purpose of this study was to investigate whether dynamic contrast enhanced MRI (DCE-MRI) data, both pharmacokinetic and empirical, can predict, prior to neoadjuvant chemotherapy, which patients are likely to have a shorter disease free survival (DFS) and overall survival (OS) interval following surgery. Traditional prognostic parameters were also included in the survival analysis. Consequently, a comparison of the prognostic value could be made between all the parameters studied. MR examinations were conducted on a 1.5 T system in 68 patients prior to the initiation of neoadjuvant chemotherapy. DCE-MRI consisted of a fast spoiled gradient echo sequence acquired over 35 phases with a mean temporal resolution of 11.3 s. Both pharmacokinetic and empirical parameters were derived from the DCE-MRI data. Kaplan–Meier survival plots were generated for each parameter and group comparisons were made utilising logrank tests. The results from the 54 patients entered into the univariate survival analysis demonstrated that traditional prognostic parameters (tumour grade, hormonal status and size), empirical parameters (maximum enhancement index, enhancement index at 30 s, area under the curve and initial slope) and adjuvant therapies demonstrated significant differences in survival intervals. Further multivariate Cox regression survival analysis revealed that empirical enhancement parameters contributed the greatest prediction of both DFS and OS in the resulting models. In conclusion, this study has demonstrated that in patients who exhibit high levels of perfusion and vessel permeability pre-treatment, evidenced by elevated empirical DCE-MRI parameters, a significantly lower disease free survival and overall survival can be expected.