Hyperthermia treatment planning including convective flow in cerebrospinal fluid for brain tumour hyperthermia treatment using a novel dedicated paediatric brain applicator

Hyperthermia therapy (40–44 \ub0C) is a promising option to increase efficacy of radiotherapy/chemotherapy for brain tumours, in particular paediatric brain tumours. The Chalmers Hyperthermia Helmet is developed for this purpose. Hyperthermia treatment planning is required for treatment optimisation, but current planning systems do not involve a physically correct model of cerebrospinal fluid (CSF). This study investigates the necessity of fluid modelling for treatment planning. We made treatments plans using the Helmet for both pre-operative and post-operative cases, comparing temperature distributions predicted with three CSF models: A convective “fluid” model, a non-convective “solid” CSF model, and CSF models with increased effective thermal conductivity (“high-k”). Treatment plans were evaluated by T90, T50 and T10 target temperatures and treatment-limiting hot spots. Adequate heating is possible with the helmet. In the pre-operative case, treatment plan quality was comparable for all three models. In the post-operative case, the high-k models were more accurate than the solid model. Predictions to within \ub11 \ub0C were obtained by a 10–20-fold increased effective thermal conductivity. Accurate modelling of the temperature in CSF requires fluid dynamics, but modelling CSF as a solid with enhanced effective thermal conductivity might be a practical alternative for a convective fluid model for many applications

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

Temperature and thermal dose during radiotherapy and hyperthermia for recurrent breast cancer are related to clinical outcome and thermal toxicity: a systematic review

Objective: Hyperthermia therapy (HT), heating tumors to 40–45 °C, is a known radiotherapy (RT) and chemotherapy sensitizer. The additional benefit of HT to RT for recurrent breast cancer has been proven in multiple randomized trials. However, published outcome after RT + HT varies widely. We performed a systematic review to investigate whether there is a relationship between achieved HT dose and clinical outcome and thermal toxicity for patients with recurrent breast cancer treated with RT + HT. Method: Four databases, EMBASE, PubMed, Cochrane library and clinicaltrials.gov, were searched with the terms breast, radiotherapy, hyperthermia therapy and their synonyms. Final search was performed on 3 April 2019. Twenty-two articles were included in the systematic review, reporting on 2330 patients with breast cancer treated with RT + HT. Results: Thirty-two HT parameters were tested for a relationship with clinical outcome. In studies reporting a relationship, the relationship was significant for complete response in 10/15 studies, in 10/13 studies for duration of local control, in 2/2 studies for overall survival and in 7/11 studies for thermal toxicity. Patients who received high thermal dose had on average 34% (range 27%–53%) more complete responses than patients who received low thermal dose. Patients who achieved higher HT parameters had increased odds/probability on improved clinical outcome and on thermal toxicity. Conclusion: Temperature and thermal dose during HT had significant influence on complete response, duration of local control, overall survival and thermal toxicity of patients with recurrent breast cancer treated with RT + HT. Higher temperature and thermal dose improved outcome, while higher maximum temperature increased incidence of thermal toxicity

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

Analysis of clinical data to determine the minimum number of sensors required for adequate skin temperature monitoring of superficial hyperthermia treatments

Purpose: Tumor response and treatment toxicity are related to minimum and maximum tissue temperatures during hyperthermia, respectively. Using a large set of clinical data, we analyzed the number of sensors required to adequately monitor skin temperature during superficial hyperthermia treatment of breast cancer patients. Methods: Hyperthermia treatments monitored with &gt;60 stationary temperature sensors were selected from a database of patients with recurrent breast cancer treated with re-irradiation (23 7 2 Gy) and hyperthermia using single 434 MHz applicators (effective field size 351–396 cm2). Reduced temperature monitoring schemes involved randomly selected subsets of stationary skin sensors, and another subset simulating continuous thermal mapping of the skin. Temperature differences (ΔT) between subsets and complete sets of sensors were evaluated in terms of overall minimum (Tmin) and maximum (Tmax) temperature, as well as T90 and T10. Results: Eighty patients were included yielding a total of 400 hyperthermia sessions. Median ΔT was 50 sensors were used. Subsets of 50 sensors were used. Thermal profiles (8–21 probes) yielded a median ΔT &lt; 0.01 \ub0C for T90 and Tmax, with a 95%CI of −0.2 \ub0C and 0.4 \ub0C, respectively. The detection rate of Tmax≥43 \ub0C is ≥85% while using &gt;50 stationary sensors or thermal profiles. Conclusions: Adequate coverage of the skin temperature distribution during superficial hyperthermia treatment requires the use of &gt;50 stationary sensors per 400 cm2applicator. Thermal mapping is a valid alternative

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

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