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Background: PanDox is a Phase-1 trial of chemotherapeutic drug delivery to pancreatic tumors using ultrasound-mediated hyperthermia to release doxorubicin from thermally sensitive liposomes. This report describes trial-related hyperthermia simulations featuring: (i) new ultrasonic properties of human pancreatic tissues, (ii) abdomen deflections imposed by a water balloon, and (iii) respiration-driven organ motion., Methods: Pancreas heating simulations were carried out using three patient body models. Pancreas acoustic properties were varied between values found in the literature and those determined from our human tissue study. Acoustic beam distortion was assessed with and without balloon-induced abdomen deformation. Target heating was assessed for static, normal respiratory, and jet-ventilation-controlled pancreas motion., Results: Human pancreatic tumor attenuation is 63% of the literature values, so that pancreas treatments require commensurately higher input intensity to achieve adequate hyperthermia. Abdominal wall deformation decreased the peak field pressure by as much as 3.5 dB and refracted the focal spot by as much as 4.5 mm. These effects were thermally counteracted by sidelobe power deposition, so the net impact on achieving mild hyperthermia was small. Respiratory motion during moving beam hyperthermia produced localized regions overheated by more than 8.0 °C above the 4.0 °C volumetric goal. The use of jet ventilation reduced this excess to 0.7 °C and yielded temperature field uniformity that was nearly identical to having no respiratory motion., Conclusion: Realistic modeling of the ultrasonic propagation environment is critical to achieving adequate mild hyperthermia without the use of real time thermometry for targeted drug delivery in pancreatic cancer patients.

Introduction: Many small molecules and biologic therapeutics have been developed for solid tumor therapy. However, the unique physiology of tumors makes the actual delivery of these drugs into the tumor mass inefficient. Such delivery requires transport from blood vessels, across the vasculature and into and through interstitial space within a tumor. This transportation is dependent on the physiochemical properties of the therapeutic agent and the biological properties of the tumor. It was hoped the application of nanoscale drug carrier systems would solve this problem. However, issues with poor tumor accumulation and limited drug release have impeded clinical impact. In response, these carrier systems have been redesigned to be paired with targetable external mechanical stimuli which can trigger much enhanced drug release and deposition., Areas Covered: The pre-clinical and clinical progress of thermolabile drug carrier systems and the modalities used to trigger the release of their cargo are assessed., Expert Opinion: Combined application of mild hyperthermia and heat-responsive liposomal drug carriers has great potential utility. Clinical trials continue to progress this approach and serve to refine the technologies, dosing regimens and exposure parameters that will provide optimal patient benefit.

Introduction: The successful treatment of metastatic cancer is refractory to strategies employed to treat confined, primary lesions, such as surgical resection and radiation therapy, and thus must be addressed by systemic delivery of anti-cancer agents. Conventional systemically administered chemotherapeutics are often ineffective and come with severe dose-limiting toxicities., Areas Covered: This review focuses on the recent developments in systemic therapy for metastatic cancer. Firstly, the strategies employed to improve the efficacy of conventional chemotherapeutics by 'passively' and 'actively' targeting them to tumors are discussed. Secondly, recent advances in the use of biologics to better target cancer and to instigate anti-tumor immunity are reviewed. Under the label of 'biologics', antibody-therapies, T cell engaging therapies, oncolytic virotherapies and cell-based therapies are examined and evaluated., Expert Opinion: Improving specificity of action, and engaging the immune system appear to be key goals in the development of novel or reformulated anti-cancer agents for the treatment of metastatic cancer. One of the largest areas of opportunity in this field will be the identification of robust predictive biomarkers for use in conjunction with these agents. Treatment regimens that combine an agent to elicit an immune response (such as an oncolytic virus), and an agent to potentiate/mediate that immune response (such as immune checkpoint inhibitors) are predicted to be more effective than treatment with either agent alone.

Acoustic cavitation has been shown to play a key role in a wide array of novel therapeutic ultrasound applications. This paper presents a brief discussion of the physics of thermally relevant acoustic cavitation in the context of high-intensity focussed ultrasound (HIFU). Models for how different types of cavitation activity can serve to accelerate tissue heating are presented, and results suggest that the bulk of the enhanced heating effect can be attributed to the absorption of broadband acoustic emissions generated by inertial cavitation. Such emissions can be readily monitored using a passive cavitation detection (PCD) scheme and could provide a means for real-time treatment monitoring. It is also shown that the appearance of hyperechoic regions (or bright-ups) on B-mode ultrasound images constitutes neither a necessary nor a sufficient condition for inertial cavitation activity to have occurred during HIFU exposure. Once instigated at relatively large HIFU excitation amplitudes, bubble activity tends to grow unstable and to migrate toward the source transducer, causing potentially undesirable pre-focal damage. Potential means of controlling inertial cavitation activity using pulsed excitation so as to confine it to the focal region are presented, with the intention of harnessing cavitation-enhanced heating for optimal HIFU treatment delivery. The role of temperature elevation in mitigating bubble-enhanced heating effects is also discussed, along with other bubble-field effects such as multiple scattering and shielding.

High intensity focused ultrasound (HIFU) is gaining rapid clinical acceptance as a treatment modality enabling non-invasive tissue heating and ablation for numerous applications. HIFU treatments are usually carried out in a single session, often as a day case procedure, with the patient either fully conscious, lightly sedated or under light general anaesthesia. A major advantage of HIFU over other thermal ablation techniques is that there is no necessity for the transcutaneous insertion of probes into the target tissue. The high powered focused beams employed are generated from sources placed either outside the body (for treatment of tumours of the liver, kidney, breast, uterus, pancreas and bone) or in the rectum (for treatment of the prostate), and are designed to enable rapid heating of a target tissue volume, while leaving tissue in the ultrasound propagation path relatively unaffected. Given the wide-ranging applicability of HIFU, numerous extra-corporeal, transrectal and interstitial devices have been designed to optimise application-specific treatment delivery. Their principle of operation is described here, alongside an overview of the physical mechanisms governing HIFU propagation and HIFU-induced heating. Present methods of characterising HIFU fields and of quantifying HIFU exposure and its associated effects are also addressed.