Robust, planning-based targeted locoregional tumour heating in small animals.

Objective.To improve hyperthermia in clinical practice, pre-clinical hyperthermia research is essential to investigate hyperthermia effects and assess novel treatment strategies. Translating pre-clinical hyperthermia findings into clinically viable protocols requires laboratory animal treatment techniques similar to clinical hyperthermia techniques. The ALBA micro8 electromagnetic heating system (Med-logix SRL, Rome, Italy) has recently been developed to provide the targeted locoregional tumour heating currently lacking for pre-clinical research. This study evaluates the heat focusing properties of this device and its ability to induce robust locoregional tumour heating under realistic physiological conditions using simulations.Approach.Simulations were performed using the Plan2Heat treatment planning package (Amsterdam UMC, the Netherlands). First, the specific absorption rate (SAR) focus was characterised using a homogeneous phantom. Hereafter, a digital mouse model was used for the characterisation of heating robustness in a mouse. Device settings were optimised for treatment of a pancreas tumour and tested for varying circumstances. The impact of uncertainties in tissue property and perfusion values was evaluated using polynomial chaos expansion. Treatment quality and robustness were evaluated based on SAR and temperature distributions.Main results.The SAR distributions within the phantom are well-focused and can be adjusted to target any specific location. The focus size (full-width half-maximum) is a spheroid with diameters 9 mm (radially) and 20 mm (axially). The mouse model simulations show strong robustness against respiratory motion and intestine and stomach filling (∆T90≤0.14°C).Mouse positioning errors in the cranial-caudal direction lead to∆T90≤0.23°C. Uncertainties in tissue property and perfusion values were found to impact the treatment plan up to 0.56 °C (SD), with a variation onT90of 0.32 °C (1 SD).Significance.Our work shows that the pre-clinical phased-array system can provide adequate and robust locoregional heating of deep-seated target regions in mice. Using our software, robust treatment plans can be generated for pre-clinical hyperthermia research.

Radiosensitization by Hyperthermia Critically Depends on the Time Interval.

PURPOSE: Hyperthermia is a potent sensitizer of radiation therapy that improves both tumor control and survival in women with locally advanced cervical cancer (LACC). The optimal sequence and interval between hyperthermia and radiation therapy are still under debate. METHODS AND MATERIALS: We investigated the interval and sequence in vitro in cervical cancer cell lines, patient-derived organoids, and SiHa cervical cancer hind leg xenografts in athymic nude mice and compared the results with retrospective results from 58 women with LACC treated with thermoradiotherapy. RESULTS: All 3 approaches confirmed that shortening the interval between hyperthermia and radiation therapy enhanced hyperthermic radiosensitization by 2 to 8 times more DNA double-strand breaks and apoptosis and 10 to 100 times lower cell survival, delayed tumor growth in mice, and increased the 5-year survival rate of women with LACC from 22% (interval ≥80 minutes) to 54% (interval <80 minutes). In vitro and in vivo results showed that the sequence of hyperthermia and radiation therapy did not affect the outcome. CONCLUSIONS: Shortening the interval between hyperthermia and radiation therapy significantly improves treatment outcomes. The sequence of hyperthermia and radiation therapy (before or after) does not seem to matter.

Adjuvant Hyperthermic Intraperitoneal Chemotherapy in Patients With Locally Advanced Colon Cancer (COLOPEC): 5-Year Results of a Randomized Multicenter Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Whether adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) might prevent peritoneal metastases after curative surgery for high-risk colon cancer is an ongoing debate. This study aimed to determine 5-year oncologic outcomes of the randomized multicenter COLOPEC trial, which included patients with clinical or pathologic T4N0-2M0 or perforated colon cancer and randomly assigned (1:1) to either adjuvant systemic chemotherapy and HIPEC (n = 100) or adjuvant systemic chemotherapy alone (n = 102). HIPEC was performed using a one-time administration of oxaliplatin (460 mg/m2, 30 minutes, 42°C, concurrent fluorouracil/leucovorin intravenously), either simultaneously (9%) or within 5-8 weeks (91%) after primary tumor resection. Outcomes were analyzed according to the intention-to-treat principle. Long-term data were available of all 202 patients included in the COLOPEC trial, with a median follow-up of 59 months (IQR, 54.5-64.5). No significant difference was found in 5-year overall survival rate between patients assigned to adjuvant HIPEC followed by systemic chemotherapy or only adjuvant systemic chemotherapy (69.6% v 70.9%, log-rank; P = .692). Five-year peritoneal metastases rates were 63.9% and 63.2% (P = .907) and 5-year disease-free survival was 55.7% and 52.3% (log-rank; P = .875), respectively. No differences in quality-of-life outcomes were found. Our findings implicate that adjuvant HIPEC should still be performed in trial setting only.

Application of HIPEC simulations for optimizing treatment delivery strategies.

INTRODUCTION: Hyperthermic IntraPEritoneal Chemotherapy (HIPEC) aims to treat microscopic disease left after CytoReductive Surgery (CRS). Thermal enhancement depends on the temperatures achieved. Since the location of microscopic disease is unknown, a homogeneous treatment is required to completely eradicate the disease while limiting side effects. To ensure homogeneous delivery, treatment planning software has been developed. This study compares simulation results with clinical data and evaluates the impact of nine treatment strategies on thermal and drug distributions. METHODS: For comparison with clinical data, three treatment strategies were simulated with different flow rates (1600-1800mL/min) and inflow temperatures (41.6-43.6 °C). Six additional treatment strategies were simulated, varying the number of inflow catheters, flow direction, and using step-up and step-down heating strategies. Thermal homogeneity and the risk of thermal injury were evaluated. RESULTS: Simulated temperature distributions, core body temperatures, and systemic chemotherapeutic concentrations compared well with literature values. Treatment strategy was found to have a strong influence on the distributions. Additional inflow catheters could improve thermal distributions, provided flow rates are kept sufficiently high (>500 mL/min) for each catheter. High flow rates (1800 mL/min) combined with high inflow temperatures (43.6 °C) could lead to thermal damage, with CEM4310 values of up to 27 min. Step-up and step-down heating strategies allow for high temperatures with reduced risk of thermal damage. CONCLUSION: The planning software provides valuable insight into the effects of different treatment strategies on peritoneal distributions. These strategies are designed to provide homogeneous treatment delivery while limiting thermal injury to normal tissue, thereby optimizing the effectiveness of HIPEC.

Quantification of tissue property and perfusion uncertainties in hyperthermia treatment planning: Multianalysis using polynomial chaos expansion.

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.

Elevated temperatures and longer durations improve the efficacy of oxaliplatin- and mitomycin C-based hyperthermic intraperitoneal chemotherapy in a confirmed rat model for peritoneal metastasis of colorectal cancer origin.

Introduction: In 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. Methods: In 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°C or 42°C to achieve temperatures in the peritoneum of 37°C or 41°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. Results: In 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°C and 40.51-41.37°C, respectively. Treatments resulted in minimal body weight decrease (<10%) and only 7/130 rats did not reach the endpoint of 48 hours after treatment. Conclusions: Both elevated temperatures and longer treatment duration resulted in a higher platinum uptake, significantly increased apoptosis and lower proliferation in PM tumor lesions, without enhanced normal tissue toxicity. Our results demonstrated that oxaliplatin- and MMC-based HIPEC procedures are both temperature- and duration-dependent in an in vivo tumor model.

Validation of thermal dynamics during Hyperthermic IntraPEritoneal Chemotherapy simulations using a 3D-printed phantom.

Introduction: CytoReductive Surgery (CRS) followed by Hyperthermic IntraPeritoneal Chemotherapy (HIPEC) is an often used strategy in treating patients diagnosed with peritoneal metastasis (PM) originating from various origins such as gastric, colorectal and ovarian. During HIPEC treatments, a heated chemotherapeutic solution is circulated through the abdomen using several inflow and outflow catheters. Due to the complex geometry and large peritoneal volume, thermal heterogeneities can occur resulting in an unequal treatment of the peritoneal surface. This can increase the risk of recurrent disease after treatment. The OpenFoam-based treatment planning software that we developed can help understand and map these heterogeneities. Methods: In this study, we validated the thermal module of the treatment planning software with an anatomically correct 3D-printed phantom of a female peritoneum. This phantom is used in an experimental HIPEC setup in which we varied catheter positions, flow rate and inflow temperatures. In total, we considered 7 different cases. We measured the thermal distribution in 9 different regions with a total of 63 measurement points. The duration of the experiment was 30 minutes, with measurement intervals of 5 seconds. Results: Experimental data were compared to simulated thermal distributions to determine the accuracy of the software. The thermal distribution per region compared well with the simulated temperature ranges. For all cases, the absolute error was well below 0.5°C near steady-state situations and around 0.5°C, for the entire duration of the experiment. Discussion: Considering clinical data, an accuracy below 0.5°C is adequate to provide estimates of variations in local treatment temperatures and to help optimize HIPEC treatments.

Evaluation of thermal dose effect in radiofrequency-induced hyperthermia with intravesical chemotherapy for nonmuscle invasive bladder cancer.

PURPOSE: In nonmuscle invasive bladder cancer (NMIBC) patients who fail standard intravesical treatment and are unfit or unwilling to undergo a radical cystectomy, radiofrequency (RF)-induced hyperthermia combined with intravesical chemotherapy (RF-CHT) has shown promising results. We studied whether higher thermal dose improves clinical NMIBC outcome. METHODS AND MATERIALS: The cohort comprised 108 patients who started with RF-CHT between November 2013 and December 2019. Patients received intravesical mitomycin-C or epirubicin. Bladder hyperthermia was accomplished with an intravesical 915 MHz RF device guided by intravesical thermometry. We assessed the association between thermal dose parameters (including median temperature and Cumulative Equivalent Minutes of T50 at 43 °C [CEM43T50]) and complete response (CR) at six months for patients with (concomitant) carcinoma in situ (CIS), and recurrence-free survival (RFS) for patients with papillary disease. RESULTS: Median temperature and CEM43T50 per treatment were 40.9 (IQR 40.8-41.1) °C and 3.1 (IQR 0.9-2.4) minutes, respectively. Analyses showed no association between any thermal dose parameter and CR or RFS (p > 0.05). Less bladder spasms during treatment sessions was associated with increased median temperature and CEM43T50 (adjusted OR 0.01 and 0.34, both p < 0.001). CONCLUSIONS: No significant association between thermal dose and NMIBC outcome was found. Possibly thermal dose effect in patients of the current cohort exceeds a certain threshold value. On the other hand, occurrence of bladder spasms had a thermal dose limiting effect. We advise to treat patients with temperatures >40.5 °C for at least 45 min while respecting individual tolerability, including occurrence of bladder spasms.

The Relevance of High Temperatures and Short Time Intervals Between Radiation Therapy and Hyperthermia: Insights in Terms of Predicted Equivalent Enhanced Radiation Dose.

PURPOSE: The radiosensitization effect of hyperthermia can be considered and quantified as an enhanced equivalent radiation dose (EQDRT), that is, the dose needed to achieve the same effect without hyperthermia. EQDRT can be predicted using an extended linear quadratic model, with temperature-dependent parameters. Clinical data show that both the achieved temperature and time interval between radiation therapy and hyperthermia correlate with clinical outcome, but their effect on expected EQDRT is unknown and was therefore evaluated in this study. METHODS AND MATERIALS: Biological modeling was performed using our in-house developed software (X-Term), considering a 23- × 2-Gy external beam radiation scheme, as applied for patients with locally advanced cervical cancer. First, the EQDRT was calculated for homogeneous temperature levels, evaluating time intervals between 0 and 4 hours. Next, realistic heterogeneous hyperthermia treatment plans were combined with radiation therapy plans and the EQDRT was calculated for 10 patients. Furthermore, the effect of achieving 0.5°C to 1°C lower or higher temperatures was evaluated. RESULTS: EQDRT increases substantially with both increasing temperature and decreasing time interval. The effect of the time interval is most pronounced at higher temperatures (>41°C). At a typical hyperthermic temperature level of 41.5°C, an enhancement of ∼10 Gy can be realized with a 0-hour time interval, which is decreased to only ∼4 Gy enhancement with a 4-hour time interval. Most enhancement is already lost after 1 hour. Evaluation in patients predicted an average additional EQDRT (D95%) of 2.2 and 6.3 Gy for 4- and 0-hour time intervals, respectively. The effect of 0.5°C to 1°C lower or higher temperatures is most pronounced at high temperature levels and short time intervals. The additional EQDRT (D95%) ranged between 1.5 and 3.3 Gy and between 4.5 and 8.5 Gy for 4- and 0-hour time intervals, respectively. CONCLUSIONS: Biological modeling provides relevant insight into the relationship between treatment parameters and expected EQDRT. Both high temperatures and short time intervals are essential to maximize EQDRT.

Perturbation of Copper Homeostasis Sensitizes Cancer Cells to Elevated Temperature.

Temporary elevation of tumor temperature, also known as hyperthermia, is a safe and well-tolerated treatment modality. The efficacy of hyperthermia can be improved by efficient thermosensitizers, and various candidate drugs, including inhibitors of the heat stress response, have been explored in vitro and in animal models, but clinically relevant thermosensitizers are lacking. Here, we employ unbiased in silico approaches to uncover new mechanisms and compounds that could be leveraged to increase the thermosensitivity of cancer cells. We then focus on elesclomol, a well-performing compound, which amplifies cell killing by hyperthermia by 5- to 20-fold in cell lines and outperforms clinically applied chemotherapy when combined with hyperthermia in vitro. Surprisingly, our findings suggest that the thermosensitizing effects of elesclomol are independent of its previously reported modes of action but depend on copper shuttling. Importantly, we show that, like elesclomol, multiple other copper shuttlers can thermosensitize, suggesting that disturbing copper homeostasis could be a general strategy for improving the efficacy of hyperthermia.

Non-Invasive Imaging and Scoring of Peritoneal Metastases in Small Preclinical Animal Models Using Ultrasound: A Preliminary Trial.

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.

Adapt2Heat: treatment planning-assisted locoregional hyperthermia by on-line visualization, optimization and re-optimization of SAR and temperature distributions.

BACKGROUND: Hyperthermia treatment planning is increasingly used in clinical applications and recommended in quality assurance guidelines. Assistance in phase-amplitude steering during treatment requires dedicated software for on-line visualization of SAR/temperature distributions and fast re-optimization in response to hot spots. As such software tools are not yet commercially available, we developed Adapt2Heat for on-line adaptive hyperthermia treatment planning and illustrate possible application by different relevant real patient examples. METHODS: Adapt2Heat was developed as a separate module of the treatment planning software Plan2Heat. Adapt2Heat runs on a Linux operating system and was developed in C++, using the open source Qt, Qwt and VTK libraries. A graphical user interface allows interactive and flexible on-line use of hyperthermia treatment planning. Predicted SAR/temperature distributions and statistics for selected phase-amplitude settings can be visualized instantly and settings can be re-optimized manually or automatically in response to hot spots. RESULTS: Pretreatment planning E-Field, SAR and temperature calculations are performed with Plan2Heat and imported in Adapt2Heat. Examples show that Adapt2Heat can be helpful in assisting with phase-amplitude steering, e.g., by suppressing indicated hot spots. The effects of phase-amplitude adjustments on the tumor and potential hot spot locations are comprehensively visualized, allowing intuitive and flexible assistance by treatment planning during locoregional hyperthermia treatments. CONCLUSION: Adapt2Heat provides an intuitive and flexible treatment planning tool for on-line treatment planning-assisted hyperthermia. Extensive features for visualization and (re-)optimization during treatment allow practical use in many locoregional hyperthermia applications. This type of tools are indispensable for enhancing the quality of hyperthermia treatment delivery.

The role of hyperthermia in the treatment of locally advanced cervical cancer: a comprehensive review.

Radiotherapy with cisplatin (chemoradiation) is the standard treatment for women with locally advanced cervical cancer. Radiotherapy with deep hyperthermia (thermoradiation) is a well established alternative, but is rarely offered as an alternative to chemoradiation, particularly for patients in whom cisplatin is contraindicated. The scope of this review is to provide an overview of the biological rationale of hyperthermia treatment delivery, including patient workflow, and the clinical effectiveness of hyperthermia as a radiosensitizer in the treatment of cervical cancer. Hyperthermia is especially effective in hypoxic and nutrient deprived areas of the tumor where radiotherapy is less effective. Its radiosensitizing effectiveness depends on the temperature level, duration of treatment, and the time interval between radiotherapy and hyperthermia. High quality hyperthermia treatment requires an experienced team, adequate online adaptive treatment planning, and is preferably performed using a phased array radiative locoregional hyperthermia device to achieve the optimal thermal dose effect. Hyperthermia is well tolerated and generally leads to only mild toxicity, such as patient discomfort. Patients in whom cisplatin is contraindicated should therefore be referred to a hyperthermia center for thermoradiation.

Preclinical In Vivo-Models to Investigate HIPEC; Current Methodologies and Challenges.

Hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment modality for patients with peritoneal metastasis (PM) of various origins which aims for cure in combination with cytoreductive surgery (CRS). Efficacy of CRS-HIPEC depends on patient selection, tumor type, delivery technique, and treatment parameters such as temperature, carrier solution, type of drug, dosage, volume, and treatment duration. Preclinical research offers a powerful tool to investigate the impact of these parameters and to assist in designing potentially more effective treatment protocols and clinical trials. The different methodologies for peritoneal disease and HIPEC are variable. This study aims to review the objectives, methods, and clinical relevance of in vivo preclinical HIPEC studies found in the literature. In this review, recommendations are provided and possible pitfalls are discussed on the choice of type of animal and tumor model per stratified parameters and study goal. The guidelines presented in this paper can improve the clinical relevance and impact of future in vivo HIPEC experiments.

PARP1-Inhibition Sensitizes Cervical Cancer Cell Lines for Chemoradiation and Thermoradiation.

Radiotherapy plus cisplatin (chemoradiation) is standard treatment for women with locoregionally advanced cervical cancer. Both radiotherapy and cisplatin induce DNA single and double-strand breaks (SSBs and DSBs). These double-strand breaks can be repaired via two major DNA repair pathways: Classical Non-Homologous End-Joining (cNHEJ) and Homologous Recombination. Besides inducing DNA breaks, cisplatin also disrupts the cNHEJ pathway. Patients contra-indicated for cisplatin are treated with radiotherapy plus hyperthermia (thermoradiation). Hyperthermia inhibits the HR pathway. The aim of our study is to enhance chemoradiation or thermoradiation by adding PARP1-inhibition, which disrupts both the SSB repair and the Alternative NHEJ DSB repair pathway. This was studied in cervical cancer cell lines (SiHa, HeLa, C33A and CaSki) treated with hyperthermia (42 °C) ± ionizing radiation (2-6 Gy) ± cisplatin (0.3-0.5 µM) ± PARP1-inhibitor (olaparib, 4.0-5.0 µM). Clonogenic assays were performed to measure cell reproductive death. DSBs were analyzed by γ-H2AX staining and cell death by live cell imaging. Both chemoradiation and thermoradiation resulted in lower survival fractions and increased unrepaired DSBs when combined with a PARP1-inhibitor. A quadruple modality, including ionizing radiation, hyperthermia, cisplatin and PARP1-i, was not more effective than either triple modality. However, both chemoradiation and thermoradiation benefit significantly from additional treatment with PARP1-i.

Hyperthermia-Based Anti-Cancer Treatments.

Hyperthermia is an adjuvant local anti-cancer treatment using temperatures exceeding the physiologically optimal level, typically 40-43 °C for approximately one hour [...].

Effect of gastrointestinal gas on the temperature distribution in pancreatic cancer hyperthermia treatment planning.

PURPOSE: In pancreatic cancer treatment, hyperthermia can be added to increase efficacy of chemo- and/or radiotherapy. Gas in stomach, intestines and colon is often in close proximity to the target volume. We investigated the impact of variations in gastrointestinal gas (GG) on temperature distributions during simulated hyperthermia treatment (HT). METHODS: We used sets of one CT and eight cone-beam CT (CBCT) scans obtained prior to/during fractionated image-guided radiotherapy in four pancreatic cancer patients. In Plan2Heat, we simulated locoregional heating by an ALBA-4D phased array radiofrequency system and calculated temperature distributions for (i) the segmented CT (sCT), (ii) sCT with GG replaced by muscle (sCT0), (iii) sCT0 with eight different GG distributions as visible on CBCT inserted (sCTCBCT). We calculated cumulative temperature-volume histograms for the clinical target volume (CTV) for all ten temperature distributions for each patient and investigated the relationship between GG volume and change in ΔT50 (temperature increase at 50% of CTV volume). We determined location and volume of normal tissue receiving a high thermal dose. RESULTS: GG volume on CBCT varied greatly (9-991 cm3). ΔT50 increased for increasing GG volume; maximum ΔT50 difference per patient was 0.4-0.6 °C. The risk for GG-associated treatment-limiting hot spots appeared low. Normal tissue high-temperature regions mostly occurred anteriorly; their volume and maximum temperature showed moderate positive correlations with GG volume, while fat-muscle interfaces were associated with higher risks for hot spots. CONCLUSIONS: Considerable changes in volume and position of gastrointestinal gas can occur and are associated with clinically relevant tumor temperature differences.

Demonstration of treatment planning software for hyperthermic intraperitoneal chemotherapy in a rat model.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) is administered to treat residual microscopic disease after cytoreductive surgery (CRS). During HIPEC, fluid (41-43 °C) is administered and drained through a limited number of catheters, risking thermal and drug heterogeneities within the abdominal cavity that might reduce effectiveness. Treatment planning software provides a unique tool for optimizing treatment delivery. This study aimed to investigate the influence of treatment-specific parameters on the thermal and drug homogeneity in the peritoneal cavity in a computed tomography based rat model. METHOD: We developed computational fluid dynamics (CFD) software simulating the dynamic flow, temperature and drug distribution during oxaliplatin based HIPEC. The influence of location and number of catheters, flow alternations and flow rates on peritoneal temperature and drug distribution were determined. The software was validated using data from experimental rat HIPEC studies. RESULTS: The predicted core temperature and systemic oxaliplatin concentration were comparable to the values found in literature. Adequate placement of catheters, additional inflow catheters and higher flow rates reduced intraperitoneal temperature spatial variation by -1.4 °C, -2.3 °C and -1.2 °C, respectively. Flow alternations resulted in higher temperatures (up to +1.5 °C) over the peritoneal surface. Higher flow rates also reduced the spatial variation of chemotherapy concentration over the peritoneal surface resulting in a more homogeneous effective treatment dose. CONCLUSION: The presented treatment planning software provides unique insights in the dynamics during HIPEC, which enables optimization of treatment-specific parameters and provides an excellent basis for HIPEC treatment planning in human applications.

Simulating drug penetration during hyperthermic intraperitoneal chemotherapy.

Hyperthermic intraperitoneal chemotherapy (HIPEC) is administered to treat residual microscopic disease after debulking cytoreductive surgery. During HIPEC, a limited number of catheters are used to administer and drain fluid containing chemotherapy (41-43 °C), yielding heterogeneities in the peritoneum. Large heterogeneities may lead to undertreated areas, increasing the risk of recurrences. Aiming at intra-abdominal homogeneity is therefore essential to fully exploit the potential of HIPEC. More insight is needed into the extent of the heterogeneities during treatments and assess their effects on the efficacy of HIPEC. To that end we developed a computational model containing embedded tumor nodules in an environment mimicking peritoneal conditions. Tumor- and treatment-specific parameters affecting drug delivery like tumor size, tumor shape, velocity, temperature and dose were assessed using three-dimensional computational fluid dynamics (CFD) to demonstrate their effect on the drug distribution and accumulation in nodules. Clonogenic assays performed on RKO colorectal cell lines yielded the temperature-dependent IC50 values of cisplatin (19.5-6.8 micromolar for 37-43 °C), used to compare drug distributions in our computational models. Our models underlined that large nodules are more difficult to treat and that temperature and velocity are the most important factors to control the drug delivery. Moderate flow velocities, between 0.01 and 1 m/s, are optimal for the delivery of cisplatin. Furthermore, higher temperatures and higher doses increased the effective penetration depth with 69% and 54%, respectively. We plan to extend the software developed for this study toward patient-specific treatment planning software, capable of mapping and assist in reducing heterogeneous flow patterns.

Fast Adaptive Temperature-Based Re-Optimization Strategies for On-Line Hot Spot Suppression during Locoregional Hyperthermia.

BACKGROUND: Experience-based adjustments in phase-amplitude settings are applied to suppress treatment limiting hot spots that occur during locoregional hyperthermia for pelvic tumors. Treatment planning could help to further optimize treatments. The aim of this research was to develop temperature-based re-optimization strategies and compare the predicted effectiveness with clinically applied protocol/experience-based steering. METHODS: This study evaluated 22 hot spot suppressions in 16 cervical cancer patients (mean age 67 ± 13 year). As a first step, all potential hot spot locations were represented by a spherical region, with a user-specified diameter. For fast and robust calculations, the hot spot temperature was represented by a user-specified percentage of the voxels with the largest heating potential (HPP). Re-optimization maximized tumor T90, with constraints to suppress the hot spot and avoid any significant increase in other regions. Potential hot spot region diameter and HPP were varied and objective functions with and without penalty terms to prevent and minimize temperature increase at other potential hot spot locations were evaluated. Predicted effectiveness was compared with clinically applied steering results. RESULTS: All strategies showed effective hot spot suppression, without affecting tumor temperatures, similar to clinical steering. To avoid the risk of inducing new hot spots, HPP should not exceed 10%. Adding a penalty term to the objective function to minimize the temperature increase at other potential hot spot locations was most effective. Re-optimization times were typically ~10 s. CONCLUSION: Fast on-line re-optimization to suppress treatment limiting hot spots seems feasible to match effectiveness of ~30 years clinical experience and will be further evaluated in a clinical setting.