Intratumoral radiofrequency hyperthermia-enhanced direct chemotherapy of pancreatic cancer

Abstract

PurposeTo investigate the technical feasibility of using ultrasound-guided intratumoral radiofrequency hyperthermia (RFH) to enhance local chemotherapy of rat orthotopic pancreatic cancers.Materials and MethodsOrthotopic pancreatic cancer masses were established by inoculating luciferase/mCherry labeled-pancreatic cancer cells into the pancreatic tails of Lewis model rats via a laparotomy approach. Twenty-four rats with pancreatic cancer and 24 mice with subcutaneous pancreatic cancer xenografts in four study groups (n = 6/group) received various treatments: i) combination therapy of intratumoral MR imaging-heating-guidewire-mediated RFH (42oC) plus local chemotherapy (gemcitabine); ii) intratumoral chemotherapy alone; iii) RFH alone; and (iv)phosphate-buffered saline (PBS). Transcutaneous ultrasound imaging was used to guide the treatment and subsequently follow changes in tumor sizes. Bioluminescence optical imaging was performed to follow photon signal changes. Sonographic and optical findings were correlated with histology at 14 days.ResultsOptical imaging demonstrated a significantly decreased bioluminescence signal in mice with combination therapy group, compared with the other control groups (0.51±0.18 VS 1.6±0.4 VS 3.18±0.9 VS 3.5±0.96, p < 0.05). Ultrasound imaging showed the smallest tumor volumes of both mice and rat group with the combination therapy, compared with other control groups (0.62±0.16 VS 1.25±0.19 VS 2.28±0.25 VS 2.64±0.26, p < 0.05) and (0.75±0.18 VS 1.31±0.30 VS 1.61±0.28 VS 1.72±0.28, p < 0.05). Both imaging findings were confirmed by histologic correlation.ConclusionIntratumoral RFH can augment the chemotherapeutic effect in an orthotopic pancreatic cancer model.

The clinical benefit of hyperthermia in pancreatic cancer: a systematic review

“…For pancreatic cancer, the efficacy of HT has been validated in the preclinical setting. For example, in subcutaneous pancreatic cancer xenografts in rats and mice, the combination of gemcitabine and HT was more effective than gemcitabine or HT alone [35][36][37]. For pancreatic cancer patients, however, data are limited.…”

The underlying molecular mechanism of intratumoral radiofrequency hyperthermia-enhanced chemotherapy of pancreatic cancer

“…In our study, RFH can increase cell apoptosis level in murine pancreatic cancer cell lines and pancreatic cancer tumors, as manifested by flow cytometry assay, which demonstrated the highest percentage of apoptotic cells with combination therapy in in-vitro experiments. 23 Furthermore, in this study, we investigated the potential mechanisms of intratumoral RFH-enhanced chemotherapeutic effects in cancers. Our findings showed that: (a) some factors related to immune responses, such as HSP70, IL-1β, and TNF-ɑ in tumor tissues, were elevated significantly after combination therapy, indicating HSP70-dependent local immune responses may involve in the mechanisms of the therapy; (b) both in vitro and in vivo experiments showed significant changes in Bax, Bcl-2, and caspase-3 expressions in the pancreatic cancer cell groups with combination therapy, compared to other controls, suggesting caspase-3-depended cell apoptosis pathways may also involve in the enhancement of RFH-induced apoptosis.…”

“…Rat models with orthotopic pancreatic cancer were created in Lewis rats weighted 150–200 ​g and RF hyperthermia was performed as described in our previous study. 23 When the orthotopic pancreatic tumors had grown to 5–10 ​mm in diameter, six rats in each of four groups were treated by (a) intratumoral injections of gemcitabine (100-mg/kg for rats), followed by RFH at approximately 42 ​°C for 30 minutes; (b) intratumoral injection of gemcitabine alone; (c) 30-min RFH alone; and (d) injection of 100 ​μL PBS to serve as a control. All groups of rats were sacrificed 24 ​h after the treatments for tumor collection.…”

“… 21 , 22 Our group has already reported the technical feasibility of using ultrasound-guided intratumoral RFH to enhance local gemcitabine treatment of pancreatic cancer in animal models. 23 , 24 However, the mechanism for increasing the efficacy of RFH for antitumor agents remains unclear. In the present study, we attempted to investigate the associated molecular mechanisms involved in enhancing therapeutic effects by the combined treatment.…”

Deployable ultrasound applicators for endoluminal delivery of volumetric hyperthermia

“…As device development and clinical investigations progress, it may be possible to deliver hyperthermia with these deployable applicators as an adjunct to a chemotherapy regimen such as conventional FOLFIRNOX [20,84] or immunotherapy [1,2,85,86]. As supported by many key studies, the localized heat can impact the blood flow and permeability of desmoplastic tumors [5][6][7]10,87], thereby increasing drug uptake [88] and activity [11,89], or directly targeting release of thermally sensitive liposomes [16][17][18][20][21][22]80,81] or nanoparticles [13,14].…”