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Introduction: Hyperthermia treatment planning (HTP) tools can guide treatment delivery, particularly with locoregional radiative phased array systems. Uncertainties in tissue and perfusion property values presently lead to quantitative inaccuracy of HTP, leading to sub-optimal treatment. Assessment of these uncertainties would allow for better judgement of the reliability of treatment plans and improve their value for treatment guidance. However, systematically investigating the impact of all uncertainties on treatment plans is a complex, high-dimensional problem and too computationally expensive for traditional Monte Carlo approaches. This study aims to systematically quantify the treatment-plan impact of tissue property uncertainties by investigating their individual contribution to, and combined impact on predicted temperature distributions. Methods: A novel Polynomial Chaos Expansion (PCE)-based HTP uncertainty quantification was developed and applied for locoregional hyperthermia of modelled tumours in the pancreatic head, prostate, rectum, and cervix. Patient models were based on the Duke and Ella digital human models. Using Plan2Heat, treatment plans were created to optimise tumour temperature (represented by T90) for treatment using the Alba4D system. For all 25–34 modelled tissues, the impact of tissue property uncertainties was analysed individually i.e., electrical and thermal conductivity, permittivity, density, specific heat capacity and perfusion. Next, combined analyses were performed on the top 30 uncertainties with the largest impact. Results: Uncertainties in thermal conductivity and heat capacity were found to have negligible impact on the predicted temperature ( < 1 × 10 −10 °C), density and permittivity uncertainties had a small impact (< 0.3 °C). Uncertainties in electrical conductivity and perfusion can lead to large variations in predicted temperature. However, variations in muscle properties result in the largest impact at locations that could limit treatment quality, with a standard deviation up to almost 6 °C (pancreas) and 3.5 °C (prostate) for perfusion and electrical conductivity, respectively. The combined influence of all significant uncertainties leads to large variations with a standard deviation up to 9.0, 3.6, 3.7 and 4.1 °C for the pancreatic, prostate, rectal and cervical cases, respectively. Conclusion: Uncertainties in tissue and perfusion property values can have a large impact on predicted temperatures from hyperthermia treatment planning. PCE-based analysis helps to identify all major uncertainties, their impact and judge the reliability of treatment plans.

IntroductionIn patients with limited peritoneal metastasis (PM) originating from colorectal cancer, cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is a potentially curative treatment option. This combined treatment modality using HIPEC with mitomycin C (MMC) for 90 minutes proved to be superior to systemic chemotherapy alone, but no benefit of adding HIPEC to CRS alone was shown using oxaliplatin-based HIPEC during 30 minutes. We investigated the impact of treatment temperature and duration as relevant HIPEC parameters for these two chemotherapeutic agents in representative preclinical models. The temperature- and duration- dependent efficacy for both oxaliplatin and MMC was evaluated in an in vitro setting and in a representative animal model. MethodsIn 130 WAG/Rij rats, PM were established through i.p. injections of rat CC-531 colon carcinoma cells with a signature similar to the dominant treatment-resistant CMS4 type human colorectal PM. Tumor growth was monitored twice per week using ultrasound, and HIPEC was applied when most tumors were 4-6 mm. A semi-open four-inflow HIPEC setup was used to circulate oxaliplatin or MMC through the peritoneum for 30, 60 or 90 minutes with inflow temperatures of 38 degrees C or 42 degrees C to achieve temperatures in the peritoneum of 37 degrees C or 41 degrees C. Tumors, healthy tissue and blood were collected directly or 48 hours after treatment to assess the platinum uptake, level of apoptosis and proliferation and to determine the healthy tissue toxicity. ResultsIn vitro results show a temperature- and duration- dependent efficacy for both oxaliplatin and MMC in both CC-531 cells and organoids. Temperature distribution throughout the peritoneum of the rats was stable with normothermic and hyperthermic average temperatures in the peritoneum ranging from 36.95-37.63 degrees C and 40.51-41.37 degrees C, respectively. Treatments resulted in minimal body weight decrease (

Background: The peritoneum is a common site for the formation of metastases originating from several gastrointestinal and gynecological malignancies. A representative preclinical model to thoroughly explore the pathophysiological mechanisms and to study new treatment strategies is important. A major challenge for such models is defining and quantifying the (total) tumor burden in the peritoneal cavity prior to treatment, since it is preferable to use non-invasive methods. We evaluated ultrasound as a simple and easy-to-handle imaging method for this purpose. Methods: Peritoneal metastases were established in six WAG/Rij rats through i.p. injections of the colon carcinoma cell line CC-531. Using ultrasound, the location, number and size of intraperitoneal tumor nodules were determined by two independent observers. Tumor outgrowth was followed using ultrasound until the peritoneal cancer index (PCI) was ≥8. Interobserver variability and ex vivo correlation were assessed. Results: Visible peritoneal tumor nodules were formed in six WAG/Rij rats within 2–4 weeks after cell injection. In most animals, tumor nodules reached a size of 4–6 mm within 3–4 weeks, with total PCI scores ranging from 10–20. The predicted PCI scores using ultrasound ranged from 11–19 and from 8–18, for observer 1 and 2, respectively, which was quite similar to the ex vivo scores. Conclusions: Ultrasound is a reliable non-invasive method to detect intraperitoneal tumor nodules and quantify tumor outgrowth in a rat model.

Purpose or Objective: Operable patients with locoregional (LR) recurrent breast cancer at high risk for re-recurrence are treated with postoperative re-irradiation combined with hyperthermia (HT), i.e. heating the target area to 40-43 °C for one hour, in the Netherlands. Early 2015, national consensus was reached using a new standard RT dose fractionation schedule of 23x2Gy, replacing the 8x4Gy RT schedule used in our center. We investigated the impact of both postoperative re-irradiation schedules combined with HT on LR control and late toxicity in patients with LR recurrent breast cancer treated at our center. Materials and Methods: In this retrospective study, 112 women with resected LR recurrent breast cancer treated in 2010-2017 with postoperative re-irradiation combined with 4-5 weekly HT sessions were included. RT treatment consisted of 8x4Gy (n=34, twice a week) until 2014, or 23x2Gy (n=78, 5 times a week) after 2014. Due to frailty or long travel distance 5 patients received 8x4Gy after 2014. Re-irradiation was delivered using 3 consecutive different RT planning techniques. From 2010 to mid-2014 the lateral chest wall and/or regional lymph nodes areas were irradiated using two opposing AP-PA fields and the anterior chest wall with electrons, the breast was treated with two tangential fields. From mid-2014 IMRT was applied using 5-7 beam angles, and from early 2016 onward VMAT using two (counter)clockwise partial arcs. Actuarial LR control and grade 2-5 late toxicity incidence (>3 months after the first re-irradiation fraction) were analyzed. Toxicity was defined according to CTC-AE v5.0. Patients had multiple late toxicities. The cause of late toxicity might be current or previous treatments or an cumulative effect. Backward multivariable Cox regression was performed. Results: Twenty-four patients (21.4%) developed an in-field recurrence. Median FU was 43 months (range 1-107 months). Threeyear LR control was 89.4% vs. 68.7% in the 23x2Gy and 8x4Gy group, respectively (p=0.01), LR control tended to be better for the 23x2Gy group after long FU (p=0.094; Fig 1A). In multivariate analysis, distant metastasis (HR 17.6; 95%CI 5.2-60.2), lymph node involvement (HR 2.9; 95%CI 1.2-7.2), recurrence site (chest wall vs. breast; HR 4.6; 95%CI 1.8-11.6) and thermal dose (low vs. high; HR 4.1; 95%CI 1.4-11.5) were associated with LR control. Three-year late grade 2, 3 and 4 toxicity was 63%, 39% and 0% vs. 54%, 19% and 8% for 23x2Gy and 8x4Gy groups, respectively. No grade 5 late toxicity occurred. The 23x2Gy group had a trend for more grade 3-4 late toxicity (p=0.064, Fig1B). Conclusion: Patients with LR recurrent breast cancer treated with 23x2Gy postoperative re-irradiation and HT tended to have better LR control at the cost of higher incidence of grade 3-4 late toxicity compared to patients treated with 8x4Gy.

Aims: First, the aim of the study was to determine whether irreversible electroporation (IRE) is associated with heat generation in the liver and pancreas at clinical (≤1,500 V/cm) and supraclinical (>1,500 V/cm) electroporation settings; second, to assess the risk of thermal tissue damage in and adjacent to the treated volume in highly perfused versus moderately perfused parts of both organs; third, to investigate the influence of perfusion and of the presence and the orientation of a metal stent on the maximal thermal elevation (ΔTSession,max) in the tissue during an IRE session at fixed IRE settings, and finally, to determine whether the maximum temperature elevation within the IRE-subjected organ during an IRE treatment (single or multiple sessions) is reflected in the organ's surface temperature.Methods: The aims were investigated in 12 case studies conducted in five female Landrace pigs. Several IRE settings were applied for lateral (2), triangular (3), and rectangular (4) electrode configurations in the liver hilum, liver periphery, pancreas head, and pancreas tail. IRE series of 10-90 pulses were applied with pulse durations that varied from 70 μs to 90 μs and electric field strengths between 1,200 V/cm and 3,000 V/cm. In select cases, a metal stent was positioned in the bile duct at the level of the liver hilum. Temperatures were measured before, during, and after IRE in and adjacent to the treatment volumes using fiber optical temperature probes (temperature at the nucleation centers) and digital thermography (surface temperature). The occurrence of thermal damage was assumed to be at temperatures above 50 °C (ΔTSession,max ≥ 13 °C relative to body temperature of 37 °C). The temperature fluctuations at the organ surface (ΔTLocSurf) were compared to the maximum temperature elevation during an IRE treatment in the electroporation zone. In select cases, IRE was applied to tissue volumes encompassing the portal vein (PV) and a constricted and patent superior mesenteric vein (SMV) to determine the influence of the heatsink effect of PV and SMV on ΔTSession,max.Results: The median baseline temperature was 31.6 °C-36.3 °C. ΔTSession,max ranged from -1.7 °C to 25.5 °C in moderately perfused parts of the liver and pancreas, and from 0.0 °C to 5.8 °C in highly perfused parts. The median ΔTLocSurf of the liver and pancreas was 1.0 °C and 10.3 °C, respectively. Constricting the SMV in the pancreas head yielded a 0.8 °C higher ΔTSession,max. The presence of a metal stent in the liver hilum resulted in a ΔTSession,max of 19.8 °C. Stents parallel to the electrodes caused a ΔTSession,max difference of 4.2 °C relative to the perpendicular orientation.Conclusions: Depending on IRE settings and tissue type, IRE is capable of inducing considerable heating in the liver and pancreas that is sufficient to cause thermal tissue damage. More significant temperature elevations are positively correlated with increasing number of electrode pairs, electric field strength, and pulse number. Temperature elevations can be further exacerbated by the presence and orientation of metal stents. Temperature elevations at the nucleation centers are not always reflected in the organ's surface temperature. Heat sink effects caused by large vessels were minimal in some instances, possibly due to reduced blood flow caused by anesthesia.Relevance for patients: Appropriate IRE settings must be chosen based on the tissue type and the presence of stents to avoid thermal damage in healthy peritumoral tissue and to protect anatomical structures [Table: see text].