Focused Ultrasound Hyperthermia for Targeted Drug Release from Thermosensitive Liposomes: Results from a Phase I Trial.

Purpose To demonstrate the feasibility and safety of using focused ultrasound planning models to determine the treatment parameters needed to deliver volumetric mild hyperthermia for targeted drug delivery without real-time thermometry. Materials and Methods This study was part of the Targeted Doxorubicin, or TARDOX, phase I prospective trial of focused ultrasound-mediated, hyperthermia-triggered drug delivery to solid liver tumors ( ClinicalTrials.gov identifier NCT02181075). Ten participants (age range, 49-68 years; average age, 60 years; four women) were treated from March 2015 to March 2017 by using a clinically approved focused ultrasound system to release doxorubicin from lyso-thermosensitive liposomes. Ultrasonic heating of target tumors (treated volume: 11-73 cm3 [mean ± standard deviation, 50 cm3 ± 26]) was monitored in six participants by using a minimally invasive temperature sensor; four participants were treated without real-time thermometry. For all participants, CT images were used with a patient-specific hyperthermia model to define focused ultrasound treatment plans. Feasibility was assessed by comparing model-prescribed focused ultrasound powers to those implemented for treatment. Safety was assessed by evaluating MR images and biopsy specimens for evidence of thermal ablation and monitoring adverse events. Results The mean difference between predicted and implemented treatment powers was -0.1 W ± 17.7 (n = 10). No evidence of focused ultrasound-related adverse effects, including thermal ablation, was found. Conclusion In this 10-participant study, the authors confirmed the feasibility of using focused ultrasound-mediated hyperthermia planning models to define treatment parameters that safely enabled targeted, noninvasive drug delivery to liver tumors while monitored with B-mode guidance and without real-time thermometry. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Dickey and Levi-Polyachenko in this issue.

Safety and feasibility of ultrasound-triggered targeted drug delivery of doxorubicin from thermosensitive liposomes in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial.

BACKGROUND: Previous preclinical research has shown that extracorporeal devices can be used to enhance the delivery and distribution of systemically administered anticancer drugs, resulting in increased intratumoural concentrations. We aimed to assess the safety and feasibility of targeted release and enhanced delivery of doxorubicin to solid tumours from thermosensitive liposomes triggered by mild hyperthermia, induced non-invasively by focused ultrasound. METHODS: We did an open-label, single-centre, phase 1 trial in a single UK hospital. Adult patients (aged ≥18 years) with unresectable and non-ablatable primary or secondary liver tumours of any histological subtype were considered for the study. Patients received a single intravenous infusion (50 mg/m2) of lyso-thermosensitive liposomal doxorubicin (LTLD), followed by extracorporeal focused ultrasound exposure of a single target liver tumour. The trial had two parts: in part I, patients had a real-time thermometry device implanted intratumourally, whereas patients in part II proceeded without thermometry and we used a patient-specific model to predict optimal exposure parameters. We assessed tumour biopsies obtained before and after focused ultrasound exposure for doxorubicin concentration and distribution. The primary endpoint was at least a doubling of total intratumoural doxorubicin concentration in at least half of the patients treated, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT02181075, and is now closed to recruitment. FINDINGS: Between March 13, 2015, and March 27, 2017, ten patients were enrolled in the study (six patients in part I and four in part II), and received a dose of LTLD followed by focused ultrasound exposure. The treatment resulted in an average increase of 3·7 times in intratumoural biopsy doxorubicin concentrations, from an estimate of 2·34 µg/g (SD 0·93) immediately after drug infusion to 8·56 µg/g (5·69) after focused ultrasound. Increases of two to ten times were observed in seven (70%) of ten patients, satisfying the primary endpoint. Serious adverse events registered were expected grade 4 transient neutropenia in five patients and prolonged hospital stay due to unexpected grade 1 confusion in one patient. Grade 3-4 adverse events recorded were neutropenia (grade 3 in one patient and grade 4 in five patients), and grade 3 anaemia in one patient. No treatment-related deaths occurred. INTERPRETATION: The combined treatment of LTLD and non-invasive focused ultrasound hyperthermia in this study seemed to be clinically feasible, safe, and able to enhance intratumoural drug delivery, providing targeted chemo-ablative response in human liver tumours that were refractory to standard chemotherapy. FUNDING: Oxford Biomedical Research Centre, National Institute for Health Research.

Heterogeneous Tissue Characterization Using Ultrasound: A Comparison of Fractal Analysis Backscatter Models on Liver Tumors.

Assessment of tumor tissue heterogeneity via ultrasound has recently been suggested as a method for predicting early response to treatment. The ultrasound backscattering characteristics can assist in better understanding the tumor texture by highlighting the local concentration and spatial arrangement of tissue scatterers. However, it is challenging to quantify the various tissue heterogeneities ranging from fine to coarse of the echo envelope peaks in tumor texture. Local parametric fractal features extracted via maximum likelihood estimation from five well-known statistical model families are evaluated for the purpose of ultrasound tissue characterization. The fractal dimension (self-similarity measure) was used to characterize the spatial distribution of scatterers, whereas the lacunarity (sparsity measure) was applied to determine scatterer number density. Performance was assessed based on 608 cross-sectional clinical ultrasound radiofrequency images of liver tumors (230 and 378 representing respondent and non-respondent cases, respectively). Cross-validation via leave-one-tumor-out and with different k-fold methodologies using a Bayesian classifier was employed for validation. The fractal properties of the backscattered echoes based on the Nakagami model (Nkg) and its extend four-parameter Nakagami-generalized inverse Gaussian (NIG) distribution achieved best results-with nearly similar performance-in characterizing liver tumor tissue. The accuracy, sensitivity and specificity of Nkg/NIG were 85.6%/86.3%, 94.0%/96.0% and 73.0%/71.0%, respectively. Other statistical models, such as the Rician, Rayleigh and K-distribution, were found to not be as effective in characterizing subtle changes in tissue texture as an indication of response to treatment. Employing the most relevant and practical statistical model could have potential consequences for the design of an early and effective clinical therapy.

Quantification of ultrasonic texture intra-heterogeneity via volumetric stochastic modeling for tissue characterization.

Intensity variations in image texture can provide powerful quantitative information about physical properties of biological tissue. However, tissue patterns can vary according to the utilized imaging system and are intrinsically correlated to the scale of analysis. In the case of ultrasound, the Nakagami distribution is a general model of the ultrasonic backscattering envelope under various scattering conditions and densities where it can be employed for characterizing image texture, but the subtle intra-heterogeneities within a given mass are difficult to capture via this model as it works at a single spatial scale. This paper proposes a locally adaptive 3D multi-resolution Nakagami-based fractal feature descriptor that extends Nakagami-based texture analysis to accommodate subtle speckle spatial frequency tissue intensity variability in volumetric scans. Local textural fractal descriptors - which are invariant to affine intensity changes - are extracted from volumetric patches at different spatial resolutions from voxel lattice-based generated shape and scale Nakagami parameters. Using ultrasound radio-frequency datasets we found that after applying an adaptive fractal decomposition label transfer approach on top of the generated Nakagami voxels, tissue characterization results were superior to the state of art. Experimental results on real 3D ultrasonic pre-clinical and clinical datasets suggest that describing tumor intra-heterogeneity via this descriptor may facilitate improved prediction of therapy response and disease characterization.