Abstract
Abstract
Background
The dense stroma of pancreatic ductal adenocarcinomas is a major barrier to drug delivery. To increase the local drug diffusion gradient, high doses of chemotherapeutic agent doxorubicin can be released from thermally-sensitive liposomes (ThermoDox®) using ultrasound-mediated hyperthermia at the tumour target. PanDox is designed as a Phase 1 single centre study to investigate enhancing drug delivery to adult patients with non-operable pancreatic ductal adenocarcinomas. The study compares a single cycle of either conventional doxorubicin alone or ThermoDox® with focused ultrasound-induced hyperthermia for targeted drug release.
Methods
Adults with non-resectable pancreatic ductal adenocarcinoma are allocated to receive a single cycle of either doxorubicin alone (Arm A) or ThermoDox® with focused ultrasound-induced hyperthermia (Arm B), based on patient- and tumour-specific safety conditions. Participants in Arm B will undergo a general anaesthetic and pre-heating of the tumour by extra-corporal focused ultrasound (FUS). Rather than employing invasive thermometry, ultrasound parameters are derived from a patient-specific treatment planning model to reach the 41 °C target temperature for drug release. ThermoDox® is then concurrently infused with further ultrasound exposure. Tumour biopsies at the targeted site from all patients are analysed post-treatment using high performance liquid chromatography to quantify doxorubicin delivered to the tumour. The primary endpoint is defined as a statistically significant enhancement in concentration of total intra-tumoural doxorubicin, comparing samples from patients receiving liposomal drug with FUS to free drug alone. Participants are followed for 21 days post-treatment to assess secondary endpoints, including radiological assessment to measure changes in tumour activity by Positron Emission Tomography Response Criteria in Solid Tumours (PERCIST) criteria, adverse events and patient-reported symptoms.
Discussion
This early phase study builds on previous work targeting tumours in the liver to investigate whether enhancement of chemotherapy delivery using ultrasound-mediated hyperthermia can be translated to the stroma-dense environment of pancreatic ductal adenocarcinoma. If successful, it could herald a new approach towards managing these difficult-to-treat tumours.
Trial registration
ClinicalTrials.gov Identifier: NCT04852367. Registered 21st April 2022.
EudraCT number: 2019–003950-10 (Registered 2019)
Iras Project ID: 272253 (Registered 2019)
Ethics Number: 20/EE/0284.
Funder
National Institute for Health and Care Research
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Genetics,Oncology
Reference21 articles.
1. Cancer Facts & Figures. American Cancer Society. 2022. p. 23.
2. Murphy JD, Adusumilli S, Griffith K, Ray MER, Zalupski M, Lawrence TSL, et al. Full-dose gemcitabine and concurrent radiotherapy for unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys. 2007;68(3):801–8.
3. Iacobuzio-donahue CA, Fu B, Yachida S, Luo M, Abe H, Henderson CM, et al. DPC4 Gene Status of the Primary Carcinoma Correlates With Patterns of Failure in Patients With Pancreatic Cancer. J Clin Oncol. 2009;27(11):1806–13.
4. Van Cutsem E, Aerts R, Haustermans K, Topal B, Van Steenbergen W, Verslype C. Systemic treatment of pancreatic cancer. Eur J Gastroenterol Hepatol. 2004;16(3):265–74. https://doi.org/10.1097/00042737-200403000-00004.
5. Netti PA, Berk DA, Swartz MA, Grodzinsky AJ, Jain RK. Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res. 2000;60(9):2497–503.
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献