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18 pages, 40123 KiB

Open AccessArticle

The Thermal Dose of Photothermal Therapy Generates Differential Immunogenicity in Human Neuroblastoma Cells

by Palak Sekhri, Debbie K. Ledezma, Anshi Shukla, Elizabeth E. Sweeney and Rohan Fernandes

Cancers 2022, 14(6), 1447; https://doi.org/10.3390/cancers14061447 - 11 Mar 2022

Cited by 10 | Viewed by 3466

Abstract

Photothermal therapy (PTT) is an effective method for tumor eradication and has been successfully combined with immunotherapy. However, besides its cytotoxic effects, little is known about the effect of the PTT thermal dose on the immunogenicity of treated tumor cells. Therefore, we administered [...] Read more.

Photothermal therapy (PTT) is an effective method for tumor eradication and has been successfully combined with immunotherapy. However, besides its cytotoxic effects, little is known about the effect of the PTT thermal dose on the immunogenicity of treated tumor cells. Therefore, we administered a range of thermal doses using Prussian blue nanoparticle-based photothermal therapy (PBNP-PTT) and assessed their effects on tumor cell death and concomitant immunogenicity correlates in two human neuroblastoma cell lines: SH-SY5Y (MYCN-non-amplified) and LAN-1 (MYCN-amplified). PBNP-PTT generated thermal dose-dependent tumor cell killing and immunogenic cell death (ICD) in both tumor lines in vitro. However, the effect of the thermal dose on ICD and the expression of costimulatory molecules, immune checkpoint molecules, major histocompatibility complexes, an NK cell-activating ligand, and a neuroblastoma-associated antigen were significantly more pronounced in SH-SY5Y cells compared with LAN-1 cells, consistent with the high-risk phenotype of LAN-1 cells. In functional co-culture studies in vitro, T cells exhibited significantly higher cytotoxicity toward SH-SY5Y cells relative to LAN-1 cells at equivalent thermal doses. This preliminary report suggests the importance of moving past the traditional focus of using PTT solely for tumor eradication to one that considers the immunogenic effects of PTT thermal dose to facilitate its success in cancer immunotherapy. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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13 pages, 3341 KiB

Open AccessArticle

A Guide for Water Bolus Temperature Selection for Semi-Deep Head and Neck Hyperthermia Treatments Using the HYPERcollar3D Applicator

by Tomas Drizdal, Gerard C. van Rhoon, Rene F. Verhaart, Ondrej Fiser and Margarethus M. Paulides

Cancers 2021, 13(23), 6126; https://doi.org/10.3390/cancers13236126 - 5 Dec 2021

Cited by 6 | Viewed by 2299

Abstract

During hyperthermia cancer treatments, especially in semi-deep hyperthermia in the head and neck (H&N) region, the induced temperature pattern is the result of a complex interplay between energy delivery and tissue cooling. The purpose of this study was to establish a water bolus [...] Read more.

During hyperthermia cancer treatments, especially in semi-deep hyperthermia in the head and neck (H&N) region, the induced temperature pattern is the result of a complex interplay between energy delivery and tissue cooling. The purpose of this study was to establish a water bolus temperature guide for the HYPERcollar3D H&N applicator. First, we measured the HYPERcollar3D water bolus heat-transfer coefficient. Then, for 20 H&N patients and phase/amplitude settings of 93 treatments we predict the T50 for nine heat-transfer coefficients and ten water bolus temperatures ranging from 20–42.5 °C. Total power was always tuned to obtain a maximum of 44 °C in healthy tissue in all simulations. As a sensitivity study we used constant and temperature-dependent tissue cooling properties. We measured a mean heat-transfer coefficient of h = 292 W m⁻²K⁻¹ for the HYPERcollar3D water bolus. The predicted T50 shows that temperature coverage is more sensitive to the water bolus temperature than to the heat-transfer coefficient. We propose changing the water bolus temperature from 30 °C to 35 °C which leads to a predicted T50 increase of +0.17/+0.55 °C (constant/temperature-dependent) for targets with a median depth < 20 mm from the skin surface. For deeper targets, maintaining a water bolus temperature at 30 °C is proposed. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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20 pages, 11481 KiB

Open AccessArticle

Preclinical Studies in Small Animals for Advanced Drug Delivery Using Hyperthermia and Intravital Microscopy

by Marjolein I. Priester, Sergio Curto, Ann L. B. Seynhaeve, Anderson Cruz Perdomo, Mohamadreza Amin, Pierre Agnass, Milad Salimibani, Pegah Faridi, Punit Prakash, Gerard C. van Rhoon and Timo L. M. ten Hagen

Cancers 2021, 13(20), 5146; https://doi.org/10.3390/cancers13205146 - 14 Oct 2021

Cited by 6 | Viewed by 2493

Abstract

This paper presents three devices suitable for the preclinical application of hyperthermia via the simultaneous high-resolution imaging of intratumoral events. (Pre)clinical studies have confirmed that the tumor micro-environment is sensitive to the application of local mild hyperthermia. Therefore, heating is a promising adjuvant [...] Read more.

This paper presents three devices suitable for the preclinical application of hyperthermia via the simultaneous high-resolution imaging of intratumoral events. (Pre)clinical studies have confirmed that the tumor micro-environment is sensitive to the application of local mild hyperthermia. Therefore, heating is a promising adjuvant to aid the efficacy of radiotherapy or chemotherapy. More so, the application of mild hyperthermia is a useful stimulus for triggered drug release from heat-sensitive nanocarriers. The response of thermosensitive nanoparticles to hyperthermia and ensuing intratumoral kinetics are considerably complex in both space and time. To obtain better insight into intratumoral processes, longitudinal imaging (preferable in high spatial and temporal resolution) is highly informative. Our devices are based on (i) an external electric heating adaptor for the dorsal skinfold model, (ii) targeted radiofrequency application, and (iii) a microwave antenna for heating of internal tumors. These models, while of some technical complexity, significantly add to the understanding of effects of mild hyperthermia warranting implementation in research on hyperthermia. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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17 pages, 3786 KiB

Open AccessArticle

Radiation-Associated Angiosarcoma of the Breast and Chest Wall Treated with Thermography-Controlled, Contactless wIRA-Hyperthermia and Hypofractionated Re-Irradiation

by Markus Notter, Emanuel Stutz, Andreas R. Thomsen and Peter Vaupel

Cancers 2021, 13(15), 3911; https://doi.org/10.3390/cancers13153911 - 3 Aug 2021

Cited by 11 | Viewed by 5877

Abstract

Background: Radiation-associated angiosarcoma of the breast (RAASB) is a rare, challenging disease, with surgery being the accepted basic therapeutic approach. In contrast, the role of adjuvant and systemic therapies is a subject of some controversy. Local recurrence rates reported in the literature are [...] Read more.

Background: Radiation-associated angiosarcoma of the breast (RAASB) is a rare, challenging disease, with surgery being the accepted basic therapeutic approach. In contrast, the role of adjuvant and systemic therapies is a subject of some controversy. Local recurrence rates reported in the literature are mostly heterogeneous and are highly dependent on the extent of surgery. In cases of locally recurrent or unresectable RAASB, prognosis is very poor. Methods: We retrospectively report on 10 consecutive RAASB patients, most of them presenting with locally recurrent or unresectable RAASB, which were treated with thermography-controlled water-filtered infrared-A (wIRA) superficial hyperthermia (HT) immediately followed by re-irradiation (re-RT). Patients with RAASB were graded based on their tumor extent before onset of radiotherapy (RT). Results: We recorded a local control (LC) rate dependent on tumor extent ranging from a high LC rate of 100% (two of two patients) in the adjuvant setting with an R0 or R2 resection to a limited LC rate of 33% (one of three patients) in patients with inoperable, macroscopic tumor lesions. Conclusion: Combined HT and re-RT should be considered as an option (a) for adjuvant treatment of RAASB, especially in cases with positive resection margins and after surgery of local recurrence (LR), and (b) for definitive treatment of unresectable RAASB. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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16 pages, 1521 KiB

Open AccessArticle

Radiobiological Evaluation of Combined Gamma Knife Radiosurgery and Hyperthermia for Pediatric Neuro-Oncology

by Morteza Ghaderi Aram, Massimiliano Zanoli, Håkan Nordström, Iuliana Toma-Dasu, Klas Blomgren and Hana Dobšíček Trefná

Cancers 2021, 13(13), 3277; https://doi.org/10.3390/cancers13133277 - 30 Jun 2021

Cited by 5 | Viewed by 2861

Abstract

Combining radiotherapy (RT) with hyperthermia (HT) has been proven effective in the treatment of a wide range of tumours, but the combination of externally delivered, focused heat and stereotactic radiosurgery has never been investigated. We explore the potential of such treatment enhancement via [...] Read more.

Combining radiotherapy (RT) with hyperthermia (HT) has been proven effective in the treatment of a wide range of tumours, but the combination of externally delivered, focused heat and stereotactic radiosurgery has never been investigated. We explore the potential of such treatment enhancement via radiobiological modelling, specifically via the linear-quadratic (LQ) model adapted to thermoradiotherapy through modulating the radiosensitivity of temperature-dependent parameters. We extend this well-established model by incorporating oxygenation effects. To illustrate the methodology, we present a clinically relevant application in pediatric oncology, which is novel in two ways. First, it deals with medulloblastoma, the most common malignant brain tumour in children, a type of brain tumour not previously reported in the literature of thermoradiotherapy studies. Second, it makes use of the Gamma Knife for the radiotherapy part, thereby being the first of its kind in this context. Quantitative metrics like the biologically effective dose (BED) and the tumour control probability (TCP) are used to assess the efficacy of the combined plan. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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22 pages, 4383 KiB

Open AccessArticle

Efficient Heat Shock Response Affects Hyperthermia-Induced Radiosensitization in a Tumor Spheroid Control Probability Assay

by Oleg Chen, Soňa Michlíková, Lisa Eckhardt, Marit Wondrak, Adriana M. De Mendoza, Mechthild Krause, Damian D. McLeod and Leoni A. Kunz-Schughart

Cancers 2021, 13(13), 3168; https://doi.org/10.3390/cancers13133168 - 25 Jun 2021

Cited by 4 | Viewed by 3393

Abstract

Hyperthermia (HT) combined with irradiation is a well-known concept to improve the curative potential of radiotherapy. Technological progress has opened new avenues for thermoradiotherapy, even for recurrent head and neck squamous cell carcinomas (HNSCC). Preclinical evaluation of the curative radiosensitizing potential of various [...] Read more.

Hyperthermia (HT) combined with irradiation is a well-known concept to improve the curative potential of radiotherapy. Technological progress has opened new avenues for thermoradiotherapy, even for recurrent head and neck squamous cell carcinomas (HNSCC). Preclinical evaluation of the curative radiosensitizing potential of various HT regimens remains ethically, economically, and technically challenging. One key objective of our study was to refine an advanced 3-D assay setup for HT + RT research and treatment testing. For the first time, HT-induced radiosensitization was systematically examined in two differently radioresponsive HNSCC spheroid models using the unique in vitro “curative” analytical endpoint of spheroid control probability. We further investigated the cellular stress response mechanisms underlying the HT-related radiosensitization process with the aim to unravel the impact of HT-induced proteotoxic stress on the overall radioresponse. HT disrupted the proteome’s thermal stability, causing severe proteotoxic stress. It strongly enhanced radiation efficacy and affected paramount survival and stress response signaling networks. Transcriptomics, q-PCR, and western blotting data revealed that HT + RT co-treatment critically triggers the heat shock response (HSR). Pre-treatment with chemical chaperones intensified the radiosensitizing effect, thereby suppressing HT-induced Hsp27 expression. Our data suggest that HT-induced radiosensitization is adversely affected by the proteotoxic stress response. Hence, we propose the inhibition of particular heat shock proteins as a targeting strategy to improve the outcome of combinatorial HT + RT. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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20 pages, 4496 KiB

Open AccessArticle

Patient-Specific Planning for Thermal Magnetic Resonance of Glioblastoma Multiforme

by Eva Oberacker, Cecilia Diesch, Jacek Nadobny, Andre Kuehne, Peter Wust, Pirus Ghadjar and Thoralf Niendorf

Cancers 2021, 13(8), 1867; https://doi.org/10.3390/cancers13081867 - 14 Apr 2021

Cited by 10 | Viewed by 2835

Abstract

Thermal intervention is a potent sensitizer of cells to chemo- and radiotherapy in cancer treatment. Glioblastoma multiforme (GBM) is a potential clinical target, given the cancer’s aggressive nature and resistance to current treatment options. This drives research into optimization algorithms for treatment planning [...] Read more.

Thermal intervention is a potent sensitizer of cells to chemo- and radiotherapy in cancer treatment. Glioblastoma multiforme (GBM) is a potential clinical target, given the cancer’s aggressive nature and resistance to current treatment options. This drives research into optimization algorithms for treatment planning as well as radiofrequency (RF) applicator design for treatment delivery. In this work, nine clinically realistic GBM target volumes (TVs) for thermal intervention are compared using three optimization algorithms and up to ten RF applicator designs for thermal magnetic resonance. Hyperthermia treatment planning (HTP) was successfully performed for all cases, including very small, large, and even split target volumes. Minimum requirements formulated for the metrics assessing HTP outcome were met and exceeded for all patient specific cases. Results indicate a 16 channel two row arrangement to be most promising. HTP of TVs with a small extent in the cranial–caudal direction in conjunction with a large radial extent remains challenging despite the advanced optimization algorithms used. In general, deep seated targets are favorable. Overall, our findings indicate that a one-size-fits-all RF applicator might not be the ultimate approach in hyperthermia of brain tumors. It stands to reason that modular and reconfigurable RF applicator configurations might best suit the needs of targeting individual GBM geometry. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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13 pages, 945 KiB

Open AccessFeature PaperArticle

Neoadjuvant Chemoradiation Combined with Regional Hyperthermia in Locally Advanced or Recurrent Rectal Cancer

by Oliver J. Ott, Cihan Gani, Lars H. Lindner, Manfred Schmidt, Ulf Lamprecht, Sultan Abdel-Rahman, Axel Hinke, Thomas Weissmann, Arndt Hartmann, Rolf D. Issels, Daniel Zips, Claus Belka, Robert Grützmann and Rainer Fietkau

Cancers 2021, 13(6), 1279; https://doi.org/10.3390/cancers13061279 - 13 Mar 2021

Cited by 24 | Viewed by 3144

Abstract

Background: To prospectively analyze feasibility and pathological complete response (pCR) rates of neoadjuvant chemoradiotherapy combined with regional hyperthermia (RHT) in patients with locally advanced (LARC) or recurrent (LRRC) rectal cancer. Methods: between 2012 and 2018, 111 patients with UICC stage IIB-IV or any [...] Read more.

Background: To prospectively analyze feasibility and pathological complete response (pCR) rates of neoadjuvant chemoradiotherapy combined with regional hyperthermia (RHT) in patients with locally advanced (LARC) or recurrent (LRRC) rectal cancer. Methods: between 2012 and 2018, 111 patients with UICC stage IIB-IV or any locally recurrent rectal cancer were included (HyRec-Trial, ClinicalTrials.gov Identifier: NCT01716949). Patients received radiotherapy with concurrent 5-Fluororuracil (5-FU)/Capecitabine and Oxaliplatin, and RHT. Stage 1 feasibility analysis evaluated dose-limiting toxicities (DLT) after 19 patients, stage 2 after 59 evaluable patients. Analysis of the pCR rate was based on histopathological reports. Results: the feasibility rates for stages 1 and 2 were 90% (17/19) and 73% (43/59), respectively. In the intention-to-treat population the pCR rate was 19% (20/105; 90% confidence interval (CI) 13.0–26.5). In the per-protocol-analysis, complete tumor regression was seen in 28% (18/64) and 38% (3/8) of the patients with LARC and LRRC, respectively. Complete resection rates (R0) among patients with LARC and LRRC who received surgery were 99% (78/84) and 67% (8/12). Conclusions: the intensified neoadjuvant and multimodality treatment schedule was feasible and led to comparable early toxicity rates as described by other trials that used the similar chemoradiation protocol. The presented treatment regimen resulted in a very high pCR rate and appears as a promising option for patients with LRRC. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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17 pages, 1192 KiB

Open AccessArticle

Salvage-Radiation Therapy and Regional Hyperthermia for Biochemically Recurrent Prostate Cancer after Radical Prostatectomy (Results of the Planned Interim Analysis)

by Marcus Beck, Pirus Ghadjar, Felix Mehrhof, Daniel Zips, Frank Paulsen, Daniel Wegener, Susen Burock, David Kaul, Carmen Stromberger, Jacek Nadobny, Oliver J. Ott, Rainer Fietkau, Volker Budach, Peter Wust, Arndt-Christian Müller and Sebastian Zschaeck

Cancers 2021, 13(5), 1133; https://doi.org/10.3390/cancers13051133 - 6 Mar 2021

Cited by 8 | Viewed by 2640

Abstract

Efforts to improve the outcome of prostate cancer (PC) patients after radical prostatectomy (RP) include adjuvant or salvage radiation therapy (SRT), but still up to 50% of patients develop a disease progression after radiotherapy (RT). Regional hyperthermia (HT) is well-known to improve tumor [...] Read more.

Efforts to improve the outcome of prostate cancer (PC) patients after radical prostatectomy (RP) include adjuvant or salvage radiation therapy (SRT), but still up to 50% of patients develop a disease progression after radiotherapy (RT). Regional hyperthermia (HT) is well-known to improve tumor sensitivity to RT in several entities. Here we report on a planned interim analysis of tolerability and feasibility after recruitment of the first 50 patients of a trial combining SRT and HT. We conducted a prospective multicenter non-randomized Phase-II-Trial (HTProstate-NCT04159051) investigating the implementation of combined moderate-dose escalated SRT (70 Gy in 35 fractions) and locoregional deep HT (7–10 HT sessions). The primary endpoints were the rate of acute genitourinary (GU), gastrointestinal (GI), and HT-related toxicities, completed HT sessions (≥7), and SRT applications per protocol (≥95% of patients). The two-step design included a planned interim analysis for acute GU-, GI- and HT-specific toxicities to ensure patients’ safety. Between November 2016 and December 2019, 52 patients entered into the trial. After 50 patients completed therapy and three months of follow-up, we performed the planned interim analysis. 10% of patients developed acute grade 2 GU and 4% grade 2 GI toxicities. No grade ≥3 GU or GI toxicities occurred. HT-specific symptoms grade 2 and 3 were observed in 4% and 2% of all patients. Thus, the pre-specified criteria for safety and continuation of recruitment were met. Moreover, ≥7 HT treatments were applicable, indicating the combination of SRT + HT to be feasible. Evaluation of early QoL showed no significant changes. With its observed low rate of GU and GI toxicities, moderate and manageable rates of HT-specific symptoms, and good feasibility, the combined SRT + HT seems to be a promising treatment approach for biochemical recurrence after RP in PC patients. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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22 pages, 4765 KiB

Open AccessArticle

Multi-Channel RF Supervision Module for Thermal Magnetic Resonance Based Cancer Therapy

by Haopeng Han, Eva Oberacker, Andre Kuehne, Shuailin Wang, Thomas Wilhelm Eigentler, Eckhard Grass and Thoralf Niendorf

Cancers 2021, 13(5), 1001; https://doi.org/10.3390/cancers13051001 - 28 Feb 2021

Cited by 8 | Viewed by 2812

Abstract

Glioblastoma multiforme (GBM) is the most lethal and common brain tumor. Combining hyperthermia with chemotherapy and/or radiotherapy improves the survival of GBM patients. Thermal magnetic resonance (ThermalMR) is a hyperthermia variant that exploits radio frequency (RF)-induced heating to examine the role of temperature [...] Read more.

Glioblastoma multiforme (GBM) is the most lethal and common brain tumor. Combining hyperthermia with chemotherapy and/or radiotherapy improves the survival of GBM patients. Thermal magnetic resonance (ThermalMR) is a hyperthermia variant that exploits radio frequency (RF)-induced heating to examine the role of temperature in biological systems and disease. The RF signals’ power and phase need to be supervised to manage the formation of the energy focal point, accurate thermal dose control, and safety. Patient position during treatment also needs to be monitored to ensure the efficacy of the treatment and avoid damages to healthy tissue. This work reports on a multi-channel RF signal supervision module that is capable of monitoring and regulating RF signals and detecting patient motion. System characterization was performed for a broad range of frequencies. Monte-Carlo simulations were performed to examine the impact of power and phase errors on hyperthermia performance. The supervision module’s utility was demonstrated in characterizing RF power amplifiers and being a key part of a feedback control loop regulating RF signals in heating experiments. Electromagnetic field simulations were conducted to calculate the impact of patient displacement during treatment. The supervision module was experimentally tested for detecting patient motion to a submillimeter level. To conclude, this work presents a cost-effective RF supervision module that is a key component for a hyperthermia hardware system and forms a technological basis for future ThermalMR applications. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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12 pages, 2976 KiB

Open AccessArticle

Optimization of the Clinical Setting Using Numerical Simulations of the Electromagnetic Field in an Obese Patient Model for Deep Regional Hyperthermia of an 8 MHz Radiofrequency Capacitively Coupled Device in the Pelvis

by Takayuki Ohguri, Kagayaki Kuroda, Katsuya Yahara, Sota Nakahara, Sho Kakinouchi, Hirohide Itamura, Takahiro Morisaki and Yukunori Korogi

Cancers 2021, 13(5), 979; https://doi.org/10.3390/cancers13050979 - 26 Feb 2021

Cited by 5 | Viewed by 2457

Abstract

Background: The purpose of this study was to evaluate the effectiveness of the clinical setting for deep regional hyperthermia of an 8 MHz radiofrequency (RF) capacitively coupled device in the pelvis by using numerical simulations of the electromagnetic field. Methods: A three-dimensional patient [...] Read more.

Background: The purpose of this study was to evaluate the effectiveness of the clinical setting for deep regional hyperthermia of an 8 MHz radiofrequency (RF) capacitively coupled device in the pelvis by using numerical simulations of the electromagnetic field. Methods: A three-dimensional patient model of cervical cancer of the uterus in an obese patient was reconstructed with computed tomography data. The specific absorption rate (SAR) and temperature distributions among the various heating settings were evaluated using numerical simulations. Results: The averaged SAR value of the deep target tumor was similar between with or without overlay boluses (OBs), and that of the subcutaneous fat (SF) at the edges of cooling boluses with OBs was lower than that of the SF without OBs. The use of OBs reduced the overheating of the SF. The 0.5% salt solution in the OB produced the least overheated areas outside the deep target tumor compared with the other concentrations. The insertion of the intergluteal cleft (IGC) bolus could improve the temperature concentration of the deep target tumor. Conclusions: The use of OBs and the salt solution concentration in the OB were important to optimize the temperature distribution. IGC bolus might contribute to temperature optimization. Further studies with individualized numerical simulations in each patient are expected. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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14 pages, 470 KiB

Open AccessArticle

Long-Term Experience with Radiofrequency-Induced Hyperthermia Combined with Intravesical Chemotherapy for Non-Muscle Invasive Bladder Cancer

by Iris S. G. Brummelhuis, Yvonne Wimper, Hilde G. J. M. Witjes-van Os, Tom J. H. Arends, Antoine G. van der Heijden and J. Alfred Witjes

Cancers 2021, 13(3), 377; https://doi.org/10.3390/cancers13030377 - 20 Jan 2021

Cited by 15 | Viewed by 3108

Abstract

Background: The recurrence rate of non-muscle invasive bladder cancer (NMIBC) is high, despite intravesical treatments. Importantly, patients are frequently unfit or unwilling to undergo a recommended radical cystectomy when standard intravesical treatments fail, due to the substantial risk of morbidity and mortality. For [...] Read more.

Background: The recurrence rate of non-muscle invasive bladder cancer (NMIBC) is high, despite intravesical treatments. Importantly, patients are frequently unfit or unwilling to undergo a recommended radical cystectomy when standard intravesical treatments fail, due to the substantial risk of morbidity and mortality. For these patients, radiofrequency-induced hyperthermia combined with intravesical chemotherapy (RF-CHT) has shown promising results. We aim to determine treatment outcomes and assess the effect of (ablative) dose. Methods: 299 intensively pretreated patients treated with RF-CHT were included in safety analysis. Of these, 274 patients who fulfilled induction treatments were included in efficacy analysis. Six-month complete response (CR) and durable response were reported for (concomitant) carcinoma in situ (CIS) patients and recurrence-free survival (RFS) for papillary patients. Results: For CIS, six-month CR-rate was 56.0%; and durable response rates were 79.7%, 66.5%, and 40.3% at one-, two- and five-year, respectively. RFS rates for papillary patients were 77.9%, 57.5%, and 37.2%, respectively. Patients treated with ablative dose are less likely to develop recurrence (adjusted Hazard Ratio 0.54, p = 0.01), compared to adjuvant dose. Conclusions: RF-CHT is effective in NMIBC patients in whom standard intravesical treatments have failed and should be considered in patients who are unwilling or unfit to undergo radical cystectomy. Patients with CIS or residual papillary tumor at baseline benefit from ablative dose. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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18 pages, 6171 KiB

Open AccessFeature PaperArticle

Clinical Feasibility of a High-Resolution Thermal Monitoring Sheet for Superficial Hyperthermia in Breast Cancer Patients

by Akke Bakker, Remko Zweije, Henny Petra Kok, Merel Willemijn Kolff, H. J. G. Desiree van den Bongard, Manfred Schmidt, Geertjan van Tienhoven and Hans Crezee

Cancers 2020, 12(12), 3644; https://doi.org/10.3390/cancers12123644 - 4 Dec 2020

Cited by 11 | Viewed by 2311

Abstract

Background: Accurate monitoring of skin surface temperatures is necessary to ensure treatment quality during superficial hyperthermia. A high-resolution thermal monitoring sheet (TMS) was developed to monitor the skin surface temperature distribution. The influence of the TMS on applicator performance was investigated, feasibility and [...] Read more.

Background: Accurate monitoring of skin surface temperatures is necessary to ensure treatment quality during superficial hyperthermia. A high-resolution thermal monitoring sheet (TMS) was developed to monitor the skin surface temperature distribution. The influence of the TMS on applicator performance was investigated, feasibility and ability to reliably monitor the temperature distribution were evaluated in a clinical study. Methods: Phantom experiments were performed to determine the influence of the TMS on power deposition patterns, applicator efficiency, and heat transfer of the water bolus for 434 and 915 MHz applicators. Clinical feasibility was evaluated in 10 women with locoregional recurrent breast cancer. Skin surface temperatures during consecutive treatments were monitored alternatingly with either standard Amsterdam UMC thermometry or TMS. Treatments were compared using (generalized) linear mixed models. Results: The TMS did not significantly affect power deposition patterns and applicator efficiency (1–2%), the reduced heat transfer of the water boluses (51–56%) could be compensated by adjusting the water bolus flow. Skin surface temperatures were monitored reliably, and no alteration of thermal toxicity was observed compared to standard Amsterdam UMC thermometry. Conclusion: Clinical application of the TMS is feasible. Power deposition patterns and applicator efficiency were not affected. Surface temperatures were monitored reliably. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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14 pages, 3347 KiB

Open AccessArticle

A Four-Inflow Construction to Ensure Thermal Stability and Uniformity during Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Rats

by Daan R. Löke, Roxan F. C. P. A. Helderman, Jan Sijbrands, Hans M. Rodermond, Pieter J. Tanis, Nicolaas A. P. Franken, Arlene L. Oei, H. Petra Kok and Johannes Crezee

Cancers 2020, 12(12), 3516; https://doi.org/10.3390/cancers12123516 - 26 Nov 2020

Cited by 10 | Viewed by 2779

Abstract

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS) is used for treating peritoneal metastases of various origins. Present HIPEC protocols have rarely been validated for relevant parameters such as optimal agent, duration and perfusate temperature. In vitro experiments are not completely representative [...] Read more.

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS) is used for treating peritoneal metastases of various origins. Present HIPEC protocols have rarely been validated for relevant parameters such as optimal agent, duration and perfusate temperature. In vitro experiments are not completely representative of clinical circumstances. Therefore, a good preclinical in vivo HIPEC model is needed in which temperature distributions can be well-controlled and are stable throughout treatments. Methods: We designed a setup able to generate and maintain a homogeneous flow during a 90-min HIPEC procedure using our in-house developed treatment planning tools and computer aided design (CAD) techniques. Twelve rats were treated with heated phosphate-buffered saline (PBS) using two catheter setups (one vs. four- inflows) and extensive thermometry. Simulated and measured thermal distribution and core temperatures were evaluated for the different setups. Results: Overall, the four-inflow resulted in more stable and more homogeneous thermal distributions than the one-inflow, with lower standard deviations (0.79 °C vs. 1.41 °C at the outflow, respectively) and less thermal losses. The average thermal loss was 0.4 °C lower for rats treated with the four-inflow setup. Rat core temperatures were kept stable using occasional tail cooling, and rarely exceeded 39 °C. Conclusion: Increasing the number of inflow catheters from one to four resulted in increased flow and temperature homogeneity and stability. Tail cooling is an adequate technique to prevent rats from overheating during 90-min treatments. This validated design can improve accuracy in future in vivo experiments investigating the impact of relevant parameters on the efficacy of different HIPEC protocols. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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16 pages, 2411 KiB

Open AccessArticle

Impact of Number of Segmented Tissues on SAR Prediction Accuracy in Deep Pelvic Hyperthermia Treatment Planning

by Iva VilasBoas-Ribeiro, Gerard C. van Rhoon, Tomas Drizdal, Martine Franckena and Margarethus M. Paulides

Cancers 2020, 12(9), 2646; https://doi.org/10.3390/cancers12092646 - 16 Sep 2020

Cited by 11 | Viewed by 3176

Abstract

In hyperthermia, the general opinion is that pre-treatment optimization of treatment settings requires a patient-specific model. For deep pelvic hyperthermia treatment planning (HTP), tissue models comprising four tissue categories are currently discriminated. For head and neck HTP, we found that more tissues are [...] Read more.

In hyperthermia, the general opinion is that pre-treatment optimization of treatment settings requires a patient-specific model. For deep pelvic hyperthermia treatment planning (HTP), tissue models comprising four tissue categories are currently discriminated. For head and neck HTP, we found that more tissues are required for increasing accuracy. In this work, we evaluated the impact of the number of segmented tissues on the predicted specific absorption rate (SAR) for the pelvic region. Highly detailed anatomical models of five healthy volunteers were selected from a virtual database. For each model, seven lists with varying levels of segmentation detail were defined and used as an input for a modeling study. SAR changes were quantified using the change in target-to-hotspot-quotient and maximum SAR relative differences, with respect to the most detailed patient model. The main finding of this study was that the inclusion of high water content tissues in the segmentation may result in a clinically relevant impact on the SAR distribution and on the predicted hyperthermia treatment quality when considering our pre-established thresholds. In general, our results underline the current clinical segmentation protocol and help to prioritize any improvements. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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15 pages, 1622 KiB

Open AccessArticle

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Surface Malignancies: Learning Curve Based on Surgical and Oncological Outcomes

by Jerzy Mielko, Karol Rawicz-Pruszyński, Katarzyna Sędłak, Katarzyna Gęca, Magdalena Kwietniewska and Wojciech P. Polkowski

Cancers 2020, 12(9), 2387; https://doi.org/10.3390/cancers12092387 - 23 Aug 2020

Cited by 5 | Viewed by 2391

Abstract

Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a complex, highly specialized procedure used to treat peritoneal surface malignancies (PSM) [...] Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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Open AccessFeature PaperReview

External Basic Hyperthermia Devices for Preclinical Studies in Small Animals

by Marjolein I. Priester, Sergio Curto, Gerard C. van Rhoon and Timo L. M. ten Hagen

Cancers 2021, 13(18), 4628; https://doi.org/10.3390/cancers13184628 - 15 Sep 2021

Cited by 18 | Viewed by 3297

Abstract

Preclinical studies have shown that application of mild hyperthermia (40–43 °C) is a promising adjuvant to solid tumor treatment. To improve preclinical testing, enhance reproducibility, and allow comparison of the obtained results, it is crucial to have standardization of the available methods. Reproducibility [...] Read more.

Preclinical studies have shown that application of mild hyperthermia (40–43 °C) is a promising adjuvant to solid tumor treatment. To improve preclinical testing, enhance reproducibility, and allow comparison of the obtained results, it is crucial to have standardization of the available methods. Reproducibility of methods in and between research groups on the same techniques is crucial to have a better prediction of the clinical outcome and to improve new treatment strategies (for instance with heat-sensitive nanoparticles). Here we provide a preclinically oriented review on the use and applicability of basic hyperthermia systems available for solid tumor thermal treatment in small animals. The complexity of these techniques ranges from a simple, low-cost water bath approach, irradiation with light or lasers, to advanced ultrasound and capacitive heating devices. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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16 pages, 1852 KiB

Open AccessReview

Hyperthermic Intraperitoneal Chemotherapy: A Critical Review

by Wim Ceelen, Jesse Demuytere and Ignace de Hingh

Cancers 2021, 13(13), 3114; https://doi.org/10.3390/cancers13133114 - 22 Jun 2021

Cited by 23 | Viewed by 5792

Abstract

With increasing awareness amongst physicians and improved radiological imaging techniques, the peritoneal cavity is increasingly recognized as an important metastatic site in various malignancies. Prognosis of these patients is usually poor as traditional treatment including surgical resection or systemic treatment is relatively ineffective. [...] Read more.

With increasing awareness amongst physicians and improved radiological imaging techniques, the peritoneal cavity is increasingly recognized as an important metastatic site in various malignancies. Prognosis of these patients is usually poor as traditional treatment including surgical resection or systemic treatment is relatively ineffective. Intraperitoneal delivery of chemotherapeutic agents is thought to be an attractive alternative as this results in high tumor tissue concentrations with limited systemic exposure. The addition of hyperthermia aims to potentiate the anti-tumor effects of chemotherapy, resulting in the concept of heated intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal metastases as it was developed about 3 decades ago. With increasing experience, HIPEC has become a safe and accepted treatment offered in many centers around the world. However, standardization of the technique has been poor and results from clinical trials have been equivocal. As a result, the true value of HIPEC in the treatment of peritoneal metastases remains a matter of debate. The current review aims to provide a critical overview of the theoretical concept and preclinical and clinical study results, to outline areas of persisting uncertainty, and to propose a framework to better define the role of HIPEC in the treatment of peritoneal malignancies. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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Open AccessReview

Hyperthermia and Tumor Immunity

by Ather Adnan, Nina M. Muñoz, Punit Prakash, Peiman Habibollahi, Erik N. K. Cressman and Rahul A. Sheth

Cancers 2021, 13(11), 2507; https://doi.org/10.3390/cancers13112507 - 21 May 2021

Cited by 29 | Viewed by 3541

Abstract

Thermal ablation is a cornerstone in the management of cancer patients. Typically, ablation procedures are performed for patients with a solitary or oligometastatic disease with the intention of eradicating all sites of the disease. Ablation has traditionally played a less prominent role for [...] Read more.

Thermal ablation is a cornerstone in the management of cancer patients. Typically, ablation procedures are performed for patients with a solitary or oligometastatic disease with the intention of eradicating all sites of the disease. Ablation has traditionally played a less prominent role for patients with a widely metastatic disease. For such patients, attempting to treat numerous sites of disease compounds potential risks without a clear clinical benefit and, as such, a compelling justification for performing an intervention that is unlikely to alter a patient’s clinical trajectory is uncommon. However, the discovery of immune checkpoints and the development of immune checkpoint inhibitors have brought a new perspective to the relevance of local cancer therapies such as ablation for patients with a metastatic disease. It is becoming increasingly apparent that local cancer therapies can have systemic immune effects. Thus, in the new perspective of cancer care centered upon immunologic principles, there is a strong interest in exploring the utility of ablation for patients with a metastatic disease for its immunologic implications. In this review, we summarize the unmet clinical need for adjuvant interventions such as ablation to broaden the impact of systemic immunotherapies. We additionally highlight the extant preclinical and clinical data for the immunogenicity of common thermal ablation modalities. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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20 pages, 1236 KiB

Open AccessReview

Modulating the Heat Stress Response to Improve Hyperthermia-Based Anticancer Treatments

by Enzo M. Scutigliani, Yongxin Liang, Hans Crezee, Roland Kanaar and Przemek M. Krawczyk

Cancers 2021, 13(6), 1243; https://doi.org/10.3390/cancers13061243 - 12 Mar 2021

Cited by 25 | Viewed by 4307

Abstract

Cancer treatments based on mild hyperthermia (39–43 °C, HT) are applied to a widening range of cancer types, but several factors limit their efficacy and slow down more widespread adoption. These factors include difficulties in adequate heat delivery, a short therapeutic window and [...] Read more.

Cancer treatments based on mild hyperthermia (39–43 °C, HT) are applied to a widening range of cancer types, but several factors limit their efficacy and slow down more widespread adoption. These factors include difficulties in adequate heat delivery, a short therapeutic window and the acquisition of thermotolerance by cancer cells. Here, we explore the biological effects of HT, the cellular responses to these effects and their clinically-relevant consequences. We then identify the heat stress response—the cellular defense mechanism that detects and counteracts the effects of heat—as one of the major forces limiting the efficacy of HT-based therapies and propose targeting this mechanism as a potentially universal strategy for improving their efficacy. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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16 pages, 289 KiB

Open AccessReview

Histological Correlation for Radiofrequency and Microwave Ablation in the Local Control of Hepatocellular Carcinoma (HCC) before Liver Transplantation: A Comprehensive Review

by Peiman Habibollahi, Rahul A. Sheth and Erik N. K. Cressman

Cancers 2021, 13(1), 104; https://doi.org/10.3390/cancers13010104 - 31 Dec 2020

Cited by 32 | Viewed by 3647

Abstract

Radiofrequency ablation (RFA) and microwave ablation (MWA) are the most widely studied and applied ablation techniques for treating primary and secondary liver tumors. These techniques are considered curative for small hepatic tumors, with post-ablation outcomes most commonly assessed by an imaging follow up. [...] Read more.

Radiofrequency ablation (RFA) and microwave ablation (MWA) are the most widely studied and applied ablation techniques for treating primary and secondary liver tumors. These techniques are considered curative for small hepatic tumors, with post-ablation outcomes most commonly assessed by an imaging follow up. However, there is increasing evidence of a discrepancy between radiological and pathological findings when ablated lesions are evaluated following liver resection or liver transplantation. A comprehensive review of the available literature reporting the complete pathological response (cPR) following RFA and MWA was performed to estimate the success rate and identify the factors associated with treatment failure. Following RFA, cPR is reported in 26–96% of tumors compared to 57–95% with MWA. Larger tumor size and vessels larger than 3 mm adjacent to the treated tumor are the most important factors identified by previous studies associated with viable residual tumors after RFA. Correlating post-ablation radiological studies with pathological findings shows that computed tomography (CT) and magnetic resonance imaging (MRI) have low sensitivity but high specificity for detecting residual viable or recurrent hepatocellular carcinoma (HCC) tumors. There are promising recent reports combining multiprobe ablation techniques with three-dimensional treatment planning software and stereotactic-aiming instrumentation to achieve more than 90% cPR in both small and large HCC tumors. In conclusion, the reported success for achieving cPR in HCC following RFA and MWA is highly variable in different studies and decreases with increasing lesion size and unfavorable tumor characteristics. Very few studies have reported a high rate of cPR. As these studies are single-center and retrospective, they need to be further validated and reproduced in other clinical settings. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

19 pages, 1565 KiB

Open AccessReview

Clinical Performance and Future Potential of Magnetic Resonance Thermometry in Hyperthermia

by Theresa V. Feddersen, Juan A. Hernandez-Tamames, Martine Franckena, Gerard C. van Rhoon and Margarethus M. Paulides

Cancers 2021, 13(1), 31; https://doi.org/10.3390/cancers13010031 - 24 Dec 2020

Cited by 37 | Viewed by 4748

Abstract

Hyperthermia treatments in the clinic rely on accurate temperature measurements to guide treatments and evaluate clinical outcome. Currently, magnetic resonance thermometry (MRT) is the only clinical option to non-invasively measure 3D temperature distributions. In this review, we evaluate the status quo and emerging [...] Read more.

Hyperthermia treatments in the clinic rely on accurate temperature measurements to guide treatments and evaluate clinical outcome. Currently, magnetic resonance thermometry (MRT) is the only clinical option to non-invasively measure 3D temperature distributions. In this review, we evaluate the status quo and emerging approaches in this evolving technology for replacing conventional dosimetry based on intraluminal or invasively placed probes. First, we define standardized MRT performance thresholds, aiming at facilitating transparency in this field when comparing MR temperature mapping performance for the various scenarios that hyperthermia is currently applied in the clinic. This is based upon our clinical experience of treating nearly 4000 patients with superficial and deep hyperthermia. Second, we perform a systematic literature review, assessing MRT performance in (I) clinical and (II) pre-clinical papers. From (I) we identify the current clinical status of MRT, including the problems faced and from (II) we extract promising new techniques with the potential to accelerate progress. From (I) we found that the basic requirements for MRT during hyperthermia in the clinic are largely met for regions without motion, for example extremities. In more challenging regions (abdomen and thorax), progress has been stagnating after the clinical introduction of MRT-guided hyperthermia over 20 years ago. One clear difficulty for advancement is that performance is not or not uniformly reported, but also that studies often omit important details regarding their approach. Motion was found to be the common main issue hindering accurate MRT. Based on (II), we reported and highlighted promising developments to tackle the issues resulting from motion (directly or indirectly), including new developments as well as optimization of already existing strategies. Combined, these may have the potential to facilitate improvement in MRT in the form of more stable and reliable measurements via better stability and accuracy. Full article

(This article belongs to the Special Issue Hyperthermia in Cancer)

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