Optimizing drug delivery in oncology using imaging and therapeutic ultrasound

Abstract

In the recent years much progress has been made in cancer treatment. Besides the traditional therapies such as chemotherapy, surgery and radiotherapy, targeted therapy and immunotherapy are increasingly being used and have clearly contributed to the improved outcome of patients with cancer. Overall, survival of patients with cancer in the Netherlands is improving [1]. However, better survival rates have not been observed equally between cancer types. A well-known explanation is phenotypic heterogeneity in tumours and their micro-environment {2}. Because of this, some (parts of) tumours or their metastases are intrinsically less sensitive to a certain therapy. In addition, heterogeneity in the distribution of drugs can be part of the problem. Differences in drug distribution between patients (e.g. pharmacokinetic differences), but also between organs within patients and even within regions of a single tumour or metastasis, contribute to a heterogeneous treatment effect [3-5]. Furthermore, as patients survive longer, long term side effects of the treatments become increasingly relevant. First, an effective drug is only effective when it reaches the right location at the right dose. Second, a treatment can be defined as optimal when maximal efficacy is joined by minimal toxicity. With these concepts in mind, this thesis investigates two methods using therapeutic ultrasound. I. MR-HIFU hyperthermia combined with temperature sensitive liposomes containing chemotherapy II. Ultrasound and microbubble therapy Both interventions aim to optimize local drug delivery, in order to obtain a maximum therapeutic effect at the target locations, while minimizing healthy tissue damage (toxicity). To bring these therapies from studies in cells (in vitro) to patients, clinical trials in veterinary patients can help pave the road to clinical human translation. Obtaining detailed information on patient characteristics using imaging, but also by learning from data of previous patients, could help to further optimize targeted therapy and personalize cancer treatment. To conclude, this thesis describes methods to optimize drug delivery using imaging and therapeutic ultrasound and focuses on ways to achieve personalized treatment with optimal effect and minimal side effects. It demonstrates the value of multidisciplinary collaboration between both technical and clinical researchers, radiologists and oncologists and veterinary and human clinicians. Future studies should be designed with both theoretical benefit and clinical feasibility in mind. In this way, clinical translation of promising techniques will hopefully benefit future patients. 1. Siesling S, Visser O, Aarts MJ, Verhoeven RHA, Aben KKH, Dinmohamed AG, van Dijk B, van der Aa M, Louwman M, Lemmens VEPP (2019) [Fight against cancer in the Netherlands: current state of affairs] [Article in Dutch]. Ned Tijdschr Geneeskd 163:D4150. 2. Marusyk A, Almendro V, Polyak K (2012) Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer 12(5):323-334. https://doi.org/10.1038/nrc3261 3. Minchinton AI, Tannock IF (2006) Drug penetration in solid tumours. Nat Rev Cancer 6(8):583-592. https://doi.org/10.1038/nrc1893 4. Tredan O, Galmarini CM, Patel K, Tannock IF (2007) Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99(19):1441-1454. https://doi.org/10.1093/jnci/djm135 5. Garattini S, Fuso Nerini I, D'Incalci M (2018) Not only tumor but also therapy heterogeneity. Ann Oncol 29(1):13-18. https://doi.org/10.1093/annonc/mdx751