Locoregional hyperthermia of deep-seated tumours applied with capacitive and radiative systems. A simulation study

Background: Locoregional hyperthermia is applied to deep-seated tumours in the pelvic region. Two very different heating techniques are often applied: capacitive and radiative heating. In this paper, numerical simulations are applied to compare the performance of both techniques in heating of deep-seated tumours. Methods: Phantom simulations were performed for small (30 × 20 × 50 cm 3 ) and large (45 × 30 × 50 cm 3 ), homogeneous fatless and inhomogeneous fat-muscle, tissue-equivalent phantoms with a central or eccentric target region. Radiative heating was simulated with the 70 MHz AMC-4 system and capacitive heating was simulated at 13.56 MHz. Simulations were performed for small fatless, small (i.e. fat layer typically 3 cm) patients with cervix, prostate, bladder and rectum cancer. Temperature distributions were simulated using constant hyperthermic-level perfusion values with tissue constraints of 44 °C and compared for both heating techniques. Results: For the small homogeneous phantom, similar target heating was predicted with radiative and capacitive heating. For the large homogeneous phantom, most effective target heating was predicted with capacitive heating. For inhomogeneous phantoms, hot spots in the fat layer limit adequate capacitive heating, and simulated target temperatures with radiative heating were 2–4 °C higher. Patient simulations predicted therapeutic target temperatures with capacitive heating for fatless patients, but radiative heating was more robust for all tumour sites and patient sizes, yielding target temperatures 1–3 °C higher than those predicted for capacitive heating. Conclusion: Generally, radiative locoregional heating yields more favourable simulated temperature distributions for deep-seated pelvic tumours, compared with capacitive heating. Therapeutic temperatures are predicted for capacitive heating in patients with (almost) no fat

Current state of the art of regional hyperthermia treatment planning: A review

Locoregional hyperthermia, i.e. increasing the tumor temperature to 40-45 °C using an external heating device, is a very effective radio and chemosensitizer, which significantly improves clinical outcome. There is a clear thermal dose-effect relation, but the pursued optimal thermal dose of 43 °C for 1 h can often not be realized due to treatment limiting hot spots in normal tissue. Modern heating devices have a large number of independent antennas, which provides flexible power steering to optimize tumor heating and minimize hot spots, but manual selection of optimal settings is difficult. Treatment planning is a very valuable tool to improve locoregional heating. This paper reviews the developments in treatment planning software for tissue segmentation, electromagnetic field calculations, thermal modeling and optimization techniques. Over the last decade, simulation tools have become more advanced. On-line use has become possible by implementing algorithms on the graphical processing unit, which allows real-time computations. The number of applications using treatment planning is increasing rapidly and moving on from retrospective analyses towards assisting prospective clinical treatment strategies. Some clinically relevant applications will be discussed

Improved unsupervised physics-informed deep learning for intravoxel incoherent motion modeling and evaluation in pancreatic cancer patients

${\bf Purpose}$: Earlier work showed that IVIM-NET$_{orig}$, an unsupervised physics-informed deep neural network, was more accurate than other state-of-the-art intravoxel-incoherent motion (IVIM) fitting approaches to DWI. This study presents an improved version: IVIM-NET$_{optim}$, and characterizes its superior performance in pancreatic ductal adenocarcinoma (PDAC) patients. ${\bf Method}$: In simulations (SNR=20), the accuracy, independence and consistency of IVIM-NET were evaluated for combinations of hyperparameters (fit S0, constraints, network architecture, # hidden layers, dropout, batch normalization, learning rate), by calculating the NRMSE, Spearman's $\rho$, and the coefficient of variation (CV$_{NET}$), respectively. The best performing network, IVIM-NET$_{optim}$ was compared to least squares (LS) and a Bayesian approach at different SNRs. IVIM-NET$_{optim}$'s performance was evaluated in 23 PDAC patients. 14 of the patients received no treatment between scan sessions and 9 received chemoradiotherapy between sessions. Intersession within-subject standard deviations (wSD) and treatment-induced changes were assessed. ${\bf Results}$: In simulations, IVIM-NET$_{optim}$ outperformed IVIM-NET$_{orig}$ in accuracy (NRMSE(D)=0.18 vs 0.20; NMRSE(f)=0.22 vs 0.27; NMRSE(D*)=0.39 vs 0.39), independence ($\rho$(D*,f)=0.22 vs 0.74) and consistency (CV$_{NET}$ (D)=0.01 vs 0.10; CV$_{NET}$ (f)=0.02 vs 0.05; CV$_{NET}$ (D*)=0.04 vs 0.11). IVIM-NET$_{optim}$ showed superior performance to the LS and Bayesian approaches at SNRs<50. In vivo, IVIM-NET$_{optim}$ sshowed significantly less noisy parameter maps with lower wSD for D and f than the alternatives. In the treated cohort, IVIM-NET$_{optim}$ detected the most individual patients with significant parameter changes compared to day-to-day variations. ${\bf Conclusion}$: IVIM-NET$_{optim}$ is recommended for IVIM fitting to DWI data

Biological modelling of the radiation dose escalation effect of regional hyperthermia in cervical cancer

Background Locoregional hyperthermia combined with radiotherapy significantly improves locoregional control and overall survival for cervical tumors compared to radiotherapy alone. In this study biological modelling is applied to quantify the effect of radiosensitization for three cervical cancer patients to evaluate the improvement in equivalent dose for the combination treatment with radiotherapy and hyperthermia. Methods The Linear-Quadratic (LQ) model extended with temperature-dependent LQ-parameters α and β was used to model radiosensitization by hyperthermia and to calculate the conventional radiation dose that is equivalent in biological effect to the combined radiotherapy and hyperthermia treatment. External beam radiotherapy planning was performed based on a prescription dose of 46Gy in 23 fractions of 2Gy. Hyperthermia treatment using the AMC-4 system was simulated based on the actual optimized system settings used during treatment. Results The simulated hyperthermia treatments for the 3 patients yielded a T50 of 40.1 °C, 40.5 °C, 41.1 °C and a T90 of 39.2 °C, 39.7 °C, 40.4 °C, respectively. The combined radiotherapy and hyperthermia treatment resulted in a D95 of 52.5Gy, 55.5Gy, 56.9Gy in the GTV, a dose escalation of 7.3–11.9Gy compared to radiotherapy alone (D95 = 45.0–45.5Gy). Conclusions This study applied biological modelling to evaluate radiosensitization by hyperthermia as a radiation-dose escalation for cervical cancer patients. This model is very useful to compare the effectiveness of different treatment schedules for combined radiotherapy and hyperthermia treatments and to guide the design of clinical studies on dose escalation using hyperthermia in a multi-modality setting

Quality assurance guidelines for interstitial hyperthermia

Quality assurance (QA) guidelines are essential to provide uniform execution of clinical hyperthermia treatments and trials. This document outlines the clinical and technical consequences of the specific properties of interstitial heat delivery and specifies recommendations for hyperthermia administration with interstitial techniques. Interstitial hyperthermia aims at tumor temperatures in the 40–44 \ub0C range as an adjunct to radiation or chemotherapy. The clinical part of this document imparts specific clinical experience of interstitial heat delivery to various tumor sites as well as recommended interstitial hyperthermia workflow and procedures. The second part describes technical requirements for quality assurance of current interstitial heating equipment including electromagnetic (radiative and capacitive) and ultrasound heating techniques. Detailed instructions are provided on characterization and documentation of the performance of interstitial hyperthermia applicators to achieve reproducible hyperthermia treatments of uniform high quality. Output power and consequent temperature rise are the key parameters for characterization of applicator performance in these QA guidelines. These characteristics determine the specific maximum tumor size and depth that can be heated adequately. The guidelines were developed by the ESHO Technical Committee with participation of senior STM members and members of the Atzelsberg Circle

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 (&lt;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.</p

Enhancing synthetic lethality of PARP-inhibitor and cisplatin in BRCA-proficient tumour cells with hyperthermia

Background: Poly-(ADP-ribose)-polymerase1 (PARP1) is involved in repair of DNA single strand breaks. PARP1-inhibitors (PARP1-i) cause an accumulation of DNA double strand breaks, which are generally repaired by homologous recombination (HR). Therefore, cancer cells harboring HR deficiencies are exceptionally sensitive to PARP1-i. For patients with HR-proficient tumors, HR can be temporarily inhibited by hyperthermia, thereby inducing synthetic lethal conditions in every tumor type. Since cisplatin is successfully used combined with hyperthermia (thermochemotherapy), we investigated the effectiveness of combining PARP1-i with thermochemotherapy. Results: The in vitro data demonstrate a decreased in cell survival after addition of PARP1-i to thermochemotherapy, which can be explained by increased DNA damage induction and less DSB repair. These in vitro findings are in line with in vivo model, in which a decreased tumor growth is observed upon addition of PARP1-i. Materials and Methods: Survival of three HR-proficient cell lines after cisplatin, hyperthermia and/or PARP1-i was studied. Cell cycle analyses, quantification of γ-H2AX foci and apoptotic assays were performed to understand these survival data. The effects of treatments were further evaluated by monitoring tumor responses in an in vivo rat model. Conclusions: Our results in HR-proficient cell lines suggest that PARP1-i combined with thermochemotherapy can be a promising clinical approach for all tumors independent of HR status

Quality assurance guidelines for superficial hyperthermia clinical trials: II. Technical requirements for heating devices

Quality assurance (QA) guidelines are essential to provide uniform execution of clinical trials with uniform quality hyperthermia treatments. This document outlines the requirements for appropriate QA of all current superficial heating equipment including electromagnetic (radiative and capacitive), ultrasound, and infrared heating techniques. Detailed instructions are provided how to characterize and document the performance of these hyperthermia applicators in order to apply reproducible hyperthermia treatments of uniform high quality. Earlier documents used specific absorption rate (SAR) to define and characterize applicator performance. In these QA guidelines, temperature rise is the leading parameter for characterization of applicator performance. The intention of this approach is that characterization can be achieved with affordable equipment and easy-to-implement procedures. These characteristics are essential to establish for each individual applicator the specific maximum size and depth of tumors that can be heated adequately. The guidelines in this document are supplemented with a second set of guidelines focusing on the clinical application. Both sets of guidelines were developed by the European Society for Hyperthermic Oncology (ESHO) Technical Committee with participation of senior Society of Thermal Medicine (STM) members and members of the Atzelsberg Circle

Sensitizing thermochemotherapy with a PARP1-inhibitor

Cis-diamminedichloroplatinum(II) (cisplatin, cDDP) is an effective chemotherapeutic agent that induces DNA double strand breaks (DSBs), primarily in replicating cells. Generally, such DSBs can be repaired by the classical or backup non-homologous end joining (c-NHEJ/b-NHEJ) or homologous recombination (HR). Therefore, inhibiting these pathways in cancer cells should enhance the efficiency of cDDP treatments. Indeed, inhibition of HR by hyperthermia (HT) sensitizes cancer cells to cDDP and in the Netherlands this combination is a standard treatment option for recurrent cervical cancer after previous radiotherapy. Additionally, cDDP has been demonstrated to disrupt c-NHEJ, which likely further increases the treatment efficacy. However, if one of these pathways is blocked, DSB repair functions can be sustained by the Poly-(ADP-ribose)-polymerase1 (PARP1)-dependent b-NHEJ. Therefore, disabling b-NHEJ should, in principle, further inhibit the repair of cDDP-induced DNA lesions and enhance the toxicity of thermochemotherapy. To explore this hypothesis, we treated a panel of cancer cell lines with HT, cDDP and a PARP1-i and measured various end-point relevant in cancer treatment. Our results demonstrate that PARP1-i does not considerably increase the efficacy of HT combined with standard, commonly used cDDP concentrations. However, in the presence of a PARP1-i, ten-fold lower concentration of cDDP can be used to induce similar cytotoxic effects. PARP1 inhibition may thus permit a substantial lowering of cDDP concentrations without diminishing treatment efficacy, potentially reducing systemic side effects