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3 pages, 199 KiB

Open AccessEditorial

Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation

by Stephan Bodis, Pirus Ghadjar and Gerard van Rhoon

Cancers 2022, 14(10), 2418; https://doi.org/10.3390/cancers14102418 - 13 May 2022

Cited by 2 | Viewed by 1606

Abstract

The road of acceptance of oncologic thermotherapy/hyperthermia as a synergistic modality in combination with standard oncologic therapies is still bumpy [...] Full article

(This article belongs to the Special Issue Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation)

Research

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22 pages, 4657 KiB

Open AccessArticle

The Effect of Hyperthermia and Radiotherapy Sequence on Cancer Cell Death and the Immune Phenotype of Breast Cancer Cells

by Azzaya Sengedorj, Michael Hader, Lukas Heger, Benjamin Frey, Diana Dudziak, Rainer Fietkau, Oliver J. Ott, Stephan Scheidegger, Sergio Mingo Barba, Udo S. Gaipl and Michael Rückert

Cancers 2022, 14(9), 2050; https://doi.org/10.3390/cancers14092050 - 19 Apr 2022

Cited by 16 | Viewed by 3763

Abstract

Hyperthermia (HT) is an accepted treatment for recurrent breast cancer which locally heats the tumor to 39–44 °C, and it is a very potent sensitizer for radiotherapy (RT) and chemotherapy. However, currently little is known about how HT with a distinct temperature, and [...] Read more.

Hyperthermia (HT) is an accepted treatment for recurrent breast cancer which locally heats the tumor to 39–44 °C, and it is a very potent sensitizer for radiotherapy (RT) and chemotherapy. However, currently little is known about how HT with a distinct temperature, and particularly, how the sequence of HT and RT changes the immune phenotype of breast cancer cells. Therefore, human MDA-MB-231 and MCF-7 breast cancer cells were treated with HT of different temperatures (39, 41 and 44 °C), alone and in combination with RT (2 × 5 Gy) in different sequences, with either RT or HT first, followed by the other. Tumor cell death forms and the expression of immune checkpoint molecules (ICMs) were analyzed by multicolor flow cytometry. Human monocyte-derived dendritic cells (moDCs) were differentiated and co-cultured with the treated cancer cells. In both cell lines, RT was the main stressor for cell death induction, with apoptosis being the prominent cell death form in MCF-7 cells and both apoptosis and necrosis in MDA-MB-231 cells. Here, the sequence of the combined treatments, either RT or HT, did not have a significant impact on the final outcome. The expression of all of the three examined immune suppressive ICMs, namely PD-L1, PD-L2 and HVEM, was significantly increased on MCF-7 cells 120 h after the treatment of RT with HT of any temperature. Of special interest for MDA-MB-231 cells is that only combinations of RT with HT of both 41 and 44 °C induced a significantly increased expression of PD-L2 at all examined time points (24, 48, 72, and 120 h). Generally, high dynamics of ICM expression can be observed after combined RT and HT treatments. There was no significant difference between the different sequences of treatments (either HT + RT or RT + HT) in case of the upregulation of ICMs. Furthermore, the co-culture of moDCs with tumor cells of any treatment had no impact on the expression of activation markers. We conclude that the sequence of HT and RT does not strongly affect the immune phenotype of breast cancer cells. However, when HT is combined with RT, it results in an increased expression of distinct immune suppressive ICMs that should be considered by including immune checkpoint inhibitors in multimodal tumor treatments with RT and HT. Further, combined RT and HT affects the immune system in the effector phase rather than in the priming phase. Full article

(This article belongs to the Special Issue Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation)

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16 pages, 25700 KiB

Open AccessArticle

A Novel Framework for the Optimization of Simultaneous ThermoBrachyTherapy

by Ioannis Androulakis, Rob M. C. Mestrom, Miranda E. M. C. Christianen, Inger-Karine K. Kolkman-Deurloo and Gerard C. van Rhoon

Cancers 2022, 14(6), 1425; https://doi.org/10.3390/cancers14061425 - 10 Mar 2022

Cited by 8 | Viewed by 2236

Abstract

In high-dose-rate brachytherapy (HDR-BT) for prostate cancer treatment, interstitial hyperthermia (IHT) is applied to sensitize the tumor to the radiation (RT) dose, aiming at a more efficient treatment. Simultaneous application of HDR-BT and IHT is anticipated to provide maximum radiosensitization of the tumor. [...] Read more.

In high-dose-rate brachytherapy (HDR-BT) for prostate cancer treatment, interstitial hyperthermia (IHT) is applied to sensitize the tumor to the radiation (RT) dose, aiming at a more efficient treatment. Simultaneous application of HDR-BT and IHT is anticipated to provide maximum radiosensitization of the tumor. With this rationale, the ThermoBrachyTherapy applicators have been designed and developed, enabling simultaneous irradiation and heating. In this research, we present a method to optimize the three-dimensional temperature distribution for simultaneous HDR-BT and IHT based on the resulting equivalent physical dose (EQD_phys) of the combined treatment. First, the temperature resulting from each electrode is precomputed. Then, for a given set of electrode settings and a precomputed radiation dose, the EQD_phys is calculated based on the temperature-dependent linear-quadratic model. Finally, the optimum set of electrode settings is found through an optimization algorithm. The method is applied on implant geometries and anatomical data of 10 previously irradiated patients, using reported thermoradiobiological parameters and physical doses. We found that an equal equivalent dose coverage of the target can be achieved with a physical RT dose reduction of 20% together with a significantly lower EQD_phys to the organs at risk (p-value < 0.001), even in the least favorable scenarios. As a result, simultaneous ThermoBrachyTherapy could lead to a relevant therapeutic benefit for patients with prostate cancer. Full article

(This article belongs to the Special Issue Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation)

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15 pages, 2157 KiB

Open AccessArticle

Long-Term Feasibility of 13.56 MHz Modulated Electro-Hyperthermia-Based Preoperative Thermoradiochemotherapy in Locally Advanced Rectal Cancer

by Yohan Lee, Sunghyun Kim, Hyejung Cha, Jae Hun Han, Hyun Joon Choi, Eun Go and Sei Hwan You

Cancers 2022, 14(5), 1271; https://doi.org/10.3390/cancers14051271 - 1 Mar 2022

Cited by 2 | Viewed by 1998

Abstract

We evaluated the effect of 13.56 MHz modulated electro-hyperthermia (mEHT) boost in neoadjuvant treatment for cT3-4- or cN-positive rectal cancer. Sixty patients who completed the mEHT feasibility trial (ClinicalTrials.gov Identifier: NCT02546596) were analyzed. Whole pelvis radiotherapy of 40 Gy, mEHT boost twice a [...] Read more.

We evaluated the effect of 13.56 MHz modulated electro-hyperthermia (mEHT) boost in neoadjuvant treatment for cT3-4- or cN-positive rectal cancer. Sixty patients who completed the mEHT feasibility trial (ClinicalTrials.gov Identifier: NCT02546596) were analyzed. Whole pelvis radiotherapy of 40 Gy, mEHT boost twice a week during radiotherapy, and surgical resection 6–8 weeks following radiotherapy were performed. The median age was 59. The median follow-up period was 58 (6–85) months. Total/near total tumor regression was observed in 20 patients (33.3%), including nine cases of complete response. T- and N-downstaging was identified in 40 (66.6%) and 53 (88.3%) patients, respectively. The 5-year overall and disease-free survival were 94.0% and 77.1%, respectively. mEHT energy of ≥3800 kJ potentially increased the overall survival (p = 0.039). The ypN-stage and perineural invasion were possible significant factors in disease-free (p = 0.003 and p = 0.005, respectively) and distant metastasis-free (p = 0.011 and p = 0.034, respectively) survival. Tumor regression, resection margin status, and other molecular genetic factors showed no correlation with survival. Although a limited analysis of a small number of patients, mEHT was feasible considering long-term survival. A relatively low dose irradiation (40 Gy) plus mEHT setting could ensure comparable clinical outcomes with possible mEHT-related prognostic features. Full article

(This article belongs to the Special Issue Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation)

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18 pages, 1046 KiB

Open AccessArticle

Present Practice of Radiative Deep Hyperthermia in Combination with Radiotherapy in Switzerland

by Emanuel Stutz, Emsad Puric, Adela Ademaj, Arnaud Künzi, Reinhardt Krcek, Olaf Timm, Dietmar Marder, Markus Notter, Susanne Rogers, Stephan Bodis and Oliver Riesterer

Cancers 2022, 14(5), 1175; https://doi.org/10.3390/cancers14051175 - 24 Feb 2022

Cited by 4 | Viewed by 2701

Abstract

Background: Moderate hyperthermia is a potent and evidence-based radiosensitizer. Several indications are reimbursed for the combination of deep hyperthermia with radiotherapy (dHT+RT). We evaluated the current practice of dHT+RT in Switzerland. Methods: All indications presented to the national hyperthermia tumor board for dHT [...] Read more.

Background: Moderate hyperthermia is a potent and evidence-based radiosensitizer. Several indications are reimbursed for the combination of deep hyperthermia with radiotherapy (dHT+RT). We evaluated the current practice of dHT+RT in Switzerland. Methods: All indications presented to the national hyperthermia tumor board for dHT between January 2017 and June 2021 were evaluated and treatment schedules were analyzed using descriptive statistics. Results: Of 183 patients presented at the hyperthermia tumor board, 71.6% were accepted and 54.1% (99/183) finally received dHT. The most commonly reimbursed dHT indications were “local recurrence and compression” (20%), rectal (14.7%) and bladder (13.7%) cancer, respectively. For 25.3% of patients, an individual request for insurance cover was necessary. 47.4% of patients were treated with curative intent; 36.8% were in-house patients and 63.2% were referred from other hospitals. Conclusions: Approximately two thirds of patients were referred for dHT+RT from external hospitals, indicating a general demand for dHT in Switzerland. The patterns of care were diverse with respect to treatment indication. To the best of our knowledge, this study shows for the first time the pattern of care in a national cohort treated with dHT+RT. This insight will serve as the basis for a national strategy to evaluate and expand the evidence for dHT. Full article

(This article belongs to the Special Issue Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation)

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15 pages, 1616 KiB

Open AccessArticle

Long-Term Outcome in a Phase II Study of Regional Hyperthermia Added to Preoperative Radiochemotherapy in Locally Advanced and Recurrent Rectal Adenocarcinomas

by Baard-Christian Schem, Frank Pfeffer, Martin Anton Ott, Johan N. Wiig, Nils Sletteskog, Torbjørn Frøystein, Mette Pernille Myklebust, Sabine Leh, Olav Dahl and Olav Mella

Cancers 2022, 14(3), 705; https://doi.org/10.3390/cancers14030705 - 29 Jan 2022

Cited by 5 | Viewed by 2254

Abstract

Hyperthermia was added to standard preoperative chemoradiation for rectal adenocarcinomas in a phase II study. Patients with T3-4 N0-2 M0 rectal cancer or local recurrences were included. Radiation dose was 54 Gy combined with capecitabine 825 mg/m² × 2 daily and once [...] Read more.

Hyperthermia was added to standard preoperative chemoradiation for rectal adenocarcinomas in a phase II study. Patients with T3-4 N0-2 M0 rectal cancer or local recurrences were included. Radiation dose was 54 Gy combined with capecitabine 825 mg/m² × 2 daily and once weekly oxaliplatin 55 mg/m². Regional hyperthermia aimed at 41.5–42.5 °C for 60 min combined with oxaliplatin infusion. Radical surgery with total or extended TME technique, was scheduled at 6–8 weeks after radiation. From April 2003 to April 2008, a total of 49 eligible patients were recruited. Median number of hyperthermia sessions were 5.4. A total of 47 out of 49 patients (96%) had the scheduled surgery, which was clinically radical in 44 patients. Complete tumour regression occurred in 29.8% of the patients who also exhibited statistically significantly better RFS and CSS. Rate of local recurrence alone at 10 years was 9.1%, distant metastases alone occurred in 25.6%, including local recurrences 40.4%. RFS for all patients was 54.8% after 5 years and CSS was 73.5%. Patients with T50 temperatures in tumours above median 39.9 °C had better RFS, 66.7% vs. 31.3%, p = 0.047, indicating a role of hyperthermia. Toxicity was acceptable. Full article

(This article belongs to the Special Issue Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation)

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20 pages, 1248 KiB

Open AccessArticle

Effects of Modulated Electro-Hyperthermia (mEHT) on Two and Three Year Survival of Locally Advanced Cervical Cancer Patients

by Carrie Anne Minnaar, Innocent Maposa, Jeffrey Allan Kotzen and Ans Baeyens

Cancers 2022, 14(3), 656; https://doi.org/10.3390/cancers14030656 - 27 Jan 2022

Cited by 12 | Viewed by 3460

Abstract

(1) Background: Modulated electro-hyperthermia (mEHT) is a mild to moderate, capacitive-coupled heating technology that uses amplitude modulation to enhance the cell-killing effects of the treatment. We present three year survival results and a cost effectiveness analysis from an ongoing randomised controlled Phase III [...] Read more.

(1) Background: Modulated electro-hyperthermia (mEHT) is a mild to moderate, capacitive-coupled heating technology that uses amplitude modulation to enhance the cell-killing effects of the treatment. We present three year survival results and a cost effectiveness analysis from an ongoing randomised controlled Phase III trial involving 210 participants evaluating chemoradiotherapy (CRT) with/without mEHT, for the management of locally advanced cervical cancer (LACC) in a resource constrained setting (Ethics Approval: M120477/M704133; ClinicalTrials.gov ID: NCT033320690). (2) Methods: We report hazard ratios (HR); odds ratio (OR), and 95% confidence intervals (CI) for overall survival and disease free survival (DFS) at two and three years in the ongoing study. Late toxicity, quality of life (QoL), and a cost effectiveness analysis (CEA) using a Markov model are also reported. (3) Results: Disease recurrence at two and three years was significantly reduced by mEHT (HR: 0.67, 95%CI: 0.48–0.93, p = 0.017; and HR: 0.70, 95%CI: 0.51–0.98, p = 0.035; respectively). There were no significant differences in late toxicity between the groups, and QoL was significantly improved in the mEHT group. In the CEA, mEHT + CRT dominated the model over CRT alone. (4) Conclusions: CRT combined with mEHT improves QoL and DFS rates, and lowers treatment costs, without increasing toxicity in LACC patients, even in resource-constrained settings. Full article

(This article belongs to the Special Issue Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation)

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13 pages, 2891 KiB

Open AccessArticle

Intensity-Modulated Radiotherapy with Regional Hyperthermia for High-Risk Localized Prostate Carcinoma

by Sota Nakahara, Takayuki Ohguri, Sho Kakinouchi, Hirohide Itamura, Takahiro Morisaki, Subaru Tani, Katuya Yahara and Naohiro Fujimoto

Cancers 2022, 14(2), 400; https://doi.org/10.3390/cancers14020400 - 13 Jan 2022

Cited by 11 | Viewed by 2335

Abstract

Background: The purpose of this study was to evaluate the efficacy and toxicity of adding regional hyperthermia to intensity-modulated radiotherapy (IMRT) plus neoadjuvant androgen deprivation therapy (ADT) for high-risk localized prostate carcinoma. Methods: Data from 121 consecutive patients with high-risk prostate carcinoma who [...] Read more.

Background: The purpose of this study was to evaluate the efficacy and toxicity of adding regional hyperthermia to intensity-modulated radiotherapy (IMRT) plus neoadjuvant androgen deprivation therapy (ADT) for high-risk localized prostate carcinoma. Methods: Data from 121 consecutive patients with high-risk prostate carcinoma who were treated with IMRT were retrospectively analyzed. The total planned dose of IMRT was 76 Gy in 38 fractions for all patients; hyperthermia was used in 70 of 121 patients. Intra-rectal temperatures at the prostate level were measured to evaluate thermal dose. Results: Median number of heating sessions was five and the median total thermal dose of CEM43T90 was 7.5 min. Median follow-up duration was 64 months. Addition of hyperthermia to IMRT predicted better clinical relapse-free survival. Higher thermal dose with CEM43T90 (>7 min) predicted improved biochemical disease-free survival. The occurrence of acute and delayed toxicity ≥Grade 2 was not significantly different between patients with or without hyperthermia. Conclusions: IMRT plus regional hyperthermia represents a promising approach with acceptable toxicity for high-risk localized prostate carcinoma. Further studies are needed to verify the efficacy of this combined treatment. Full article

(This article belongs to the Special Issue Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation)

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17 pages, 2929 KiB

Open AccessArticle

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

by H. Petra Kok and Johannes Crezee

Cancers 2022, 14(1), 133; https://doi.org/10.3390/cancers14010133 - 28 Dec 2021

Cited by 3 | Viewed by 1617

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation)

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14 pages, 1318 KiB

Open AccessArticle

Feasibility, SAR Distribution, and Clinical Outcome upon Reirradiation and Deep Hyperthermia Using the Hypercollar3D in Head and Neck Cancer Patients

by Michiel Kroesen, Netteke van Holthe, Kemal Sumser, Dana Chitu, Rene Vernhout, Gerda Verduijn, Martine Franckena, Jose Hardillo, Gerard van Rhoon and Margarethus Paulides

Cancers 2021, 13(23), 6149; https://doi.org/10.3390/cancers13236149 - 6 Dec 2021

Cited by 10 | Viewed by 3347

Abstract

(1) Background: Head and neck cancer (HNC) patients with recurrent or second primary (SP) tumors in previously irradiated areas represent a clinical challenge. Definitive or postoperative reirradiation with or without sensitizing therapy, like chemotherapy, should be considered. As an alternative to chemotherapy, hyperthermia [...] Read more.

(1) Background: Head and neck cancer (HNC) patients with recurrent or second primary (SP) tumors in previously irradiated areas represent a clinical challenge. Definitive or postoperative reirradiation with or without sensitizing therapy, like chemotherapy, should be considered. As an alternative to chemotherapy, hyperthermia has shown to be a potent sensitizer of radiotherapy in clinical studies in the primary treatment of HNC. At our institution, we developed the Hypercollar3D, as the successor to the Hypercollar, to enable improved application of hyperthermia for deeply located HNC. In this study, we report on the feasibility and clinical outcome of patients treated with the Hypercollar3D as an adjuvant to reirradiation in recurrent or SP HNC patients; (2) Methods: We retrospectively analyzed all patients with a recurrent or SP HNC treated with reirradiation combined with hyperthermia using the Hypercollar3D between 2014 and 2018. Data on patients, tumors, and treatments were collected. Follow-up data on disease specific outcomes as well as acute and late toxicity were collected. Data were analyzed using Kaplan Meier analyses; (3) Results: Twenty-two patients with recurrent or SP HNC were included. The average mean estimated applied cfSAR to the tumor volume for the last 17 patients was 80.5 W/kg. Therefore, the novel Hypercollar3D deposits 55% more energy at the target than our previous Hypercollar applicator. In patients treated with definitive thermoradiotherapy a complete response rate of 81.8% (9/11) was observed at 12 weeks following radiotherapy. Two-year local control (LC) and overall survival (OS) were 36.4% (95% CI 17.4–55.7%) and 54.6% (95% CI 32.1–72.4%), respectively. Patients with an interval longer than 24 months from their previous radiotherapy course had an LC of 66.7% (95% CI 37.5–84.6%), whereas patients with a time interval shorter than 24 months had an LC of 14.3% (95% CI 0.7–46.5%) at 18 months (p = 0.01). Cumulative grade 3 or higher toxicity was 39.2% (95% CI 16.0–61.9%); (4) Conclusions: Reirradiation combined with deep hyperthermia in HNC patients using the novel Hypercollar3D is feasible and deposits an average cfSAR of 80.5 W/kg in the tumor volume. The treatment results in high complete response rates at 12 weeks post-treatment. Local control and local toxicity rates were comparable to those reported for recurrent or SP HNC. To further optimize the hyperthermia treatment in the future, temperature feedback is warranted to apply heat at the maximum tolerable dose without toxicity. These data support further research in hyperthermia as an adjuvant to radiotherapy, both in the recurrent as well as in the primary treatment of HNC patients. Full article

(This article belongs to the Special Issue Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation)

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16 pages, 2298 KiB

Open AccessArticle

Theoretical Evaluation of the Impact of Hyperthermia in Combination with Radiation Therapy in an Artificial Immune—Tumor-Ecosystem

by Stephan Scheidegger, Sergio Mingo Barba and Udo S. Gaipl

Cancers 2021, 13(22), 5764; https://doi.org/10.3390/cancers13225764 - 17 Nov 2021

Cited by 7 | Viewed by 2097

Abstract

There is some evidence that radiotherapy (RT) can trigger anti-tumor immune responses. In addition, hyperthermia (HT) is known to be a tumor cell radio-sensitizer. How HT could enhance the anti-tumor immune response produced by RT is still an open question. The aim of [...] Read more.

There is some evidence that radiotherapy (RT) can trigger anti-tumor immune responses. In addition, hyperthermia (HT) is known to be a tumor cell radio-sensitizer. How HT could enhance the anti-tumor immune response produced by RT is still an open question. The aim of this study is the evaluation of potential dynamic effects regarding the adaptive immune response induced by different combinations of RT fractions with HT. The adaptive immune system is considered as a trainable unit (perceptron) which compares danger signals released by necrotic or apoptotic cell death with the presence of tumor- and host tissue cell population-specific molecular patterns (antigens). To mimic the changes produced by HT such as cell radio-sensitization or increase of the blood perfusion after hyperthermia, simplistic biophysical models were included. To study the effectiveness of the different RT+HT treatments, the Tumor Control Probability (TCP) was calculated. In the considered scenarios, the major effect of HT is related to the enhancement of the cell radio-sensitivity while perfusion or heat-based effects on the immune system seem to contribute less. Moreover, no tumor vaccination effect has been observed. In the presented scenarios, HT boosts the RT cell killing but it does not fundamentally change the anti-tumor immune response. Full article

(This article belongs to the Special Issue Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation)

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24 pages, 3051 KiB

Open AccessArticle

Feasibility of Temperature Control by Electrical Impedance Tomography in Hyperthermia

by Redi Poni, Esra Neufeld, Myles Capstick, Stephan Bodis, Theodoros Samaras and Niels Kuster

Cancers 2021, 13(13), 3297; https://doi.org/10.3390/cancers13133297 - 30 Jun 2021

Cited by 7 | Viewed by 2556

Abstract

We present a simulation study investigating the feasibility of electrical impedance tomography (EIT) as a low cost, noninvasive technique for hyperthermia (HT) treatment monitoring and adaptation. Temperature rise in tissues leads to perfusion and tissue conductivity changes that can be reconstructed in 3D [...] Read more.

We present a simulation study investigating the feasibility of electrical impedance tomography (EIT) as a low cost, noninvasive technique for hyperthermia (HT) treatment monitoring and adaptation. Temperature rise in tissues leads to perfusion and tissue conductivity changes that can be reconstructed in 3D by EIT to noninvasively map temperature and perfusion. In this study, we developed reconstruction methods and investigated the achievable accuracy of EIT by simulating HT treatmentlike scenarios, using detailed anatomical models with heterogeneous conductivity distributions. The impact of the size and location of the heated region, the voltage measurement signal-to-noise ratio, and the reference model personalization and accuracy were studied. Results showed that by introducing an iterative reconstruction approach, combined with adaptive prior regions and tissue-dependent penalties, planning-based reference models, measurement-based reweighting, and physics-based constraints, it is possible to map conductivity-changes throughout the heated domain, with an accuracy of around 5% and cm-scale spatial resolution. An initial exploration of the use of multifrequency EIT to separate temperature and perfusion effects yielded promising results, indicating that temperature reconstruction accuracy can be in the order of 1 °C. Our results suggest that EIT can provide valuable real-time HT monitoring capabilities. Experimental confirmation in real-world conditions is the next step. Full article

(This article belongs to the Special Issue Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation)

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Review

Jump to: Editorial, Research

24 pages, 2039 KiB

Open AccessReview

Accurate Three-Dimensional Thermal Dosimetry and Assessment of Physiologic Response Are Essential for Optimizing Thermoradiotherapy

by Mark W. Dewhirst, James R. Oleson, John Kirkpatrick and Timothy W. Secomb

Cancers 2022, 14(7), 1701; https://doi.org/10.3390/cancers14071701 - 27 Mar 2022

Cited by 16 | Viewed by 2838

Abstract

Numerous randomized trials have revealed that hyperthermia (HT) + radiotherapy or chemotherapy improves local tumor control, progression free and overall survival vs. radiotherapy or chemotherapy alone. Despite these successes, however, some individuals fail combination therapy; not every patient will obtain maximal benefit from [...] Read more.

Numerous randomized trials have revealed that hyperthermia (HT) + radiotherapy or chemotherapy improves local tumor control, progression free and overall survival vs. radiotherapy or chemotherapy alone. Despite these successes, however, some individuals fail combination therapy; not every patient will obtain maximal benefit from HT. There are many potential reasons for failure. In this paper, we focus on how HT influences tumor hypoxia, since hypoxia negatively influences radiotherapy and chemotherapy response as well as immune surveillance. Pre-clinically, it is well established that reoxygenation of tumors in response to HT is related to the time and temperature of exposure. In most pre-clinical studies, reoxygenation occurs only during or shortly after a HT treatment. If this were the case clinically, then it would be challenging to take advantage of HT induced reoxygenation. An important question, therefore, is whether HT induced reoxygenation occurs in the clinic that is of radiobiological significance. In this review, we will discuss the influence of thermal history on reoxygenation in both human and canine cancers treated with thermoradiotherapy. Results of several clinical series show that reoxygenation is observed and persists for 24–48 h after HT. Further, reoxygenation is associated with treatment outcome in thermoradiotherapy trials as assessed by: (1) a doubling of pathologic complete response (pCR) in human soft tissue sarcomas, (2) a 14 mmHg increase in pO2 of locally advanced breast cancers achieving a clinical response vs. a 9 mmHg decrease in pO2 of locally advanced breast cancers that did not respond and (3) a significant correlation between extent of reoxygenation (as assessed by pO2 probes and hypoxia marker drug immunohistochemistry) and duration of local tumor control in canine soft tissue sarcomas. The persistence of reoxygenation out to 24–48 h post HT is distinctly different from most reported rodent studies. In these clinical series, comparison of thermal data with physiologic response shows that within the same tumor, temperatures at the higher end of the temperature distribution likely kill cells, resulting in reduced oxygen consumption rate, while lower temperatures in the same tumor improve perfusion. However, reoxygenation does not occur in all subjects, leading to significant uncertainty about the thermal–physiologic relationship. This uncertainty stems from limited knowledge about the spatiotemporal characteristics of temperature and physiologic response. We conclude with recommendations for future research with emphasis on retrieving co-registered thermal and physiologic data before and after HT in order to begin to unravel complex thermophysiologic interactions that appear to occur with thermoradiotherapy. Full article

(This article belongs to the Special Issue Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation)

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41 pages, 7883 KiB

Open AccessReview

Heterogeneous Heat Absorption Is Complementary to Radiotherapy

by Andras Szasz

Cancers 2022, 14(4), 901; https://doi.org/10.3390/cancers14040901 - 11 Feb 2022

Cited by 11 | Viewed by 3571

Abstract

(1) Background: Hyperthermia in oncology conventionally seeks the homogeneous heating of the tumor mass. The expected isothermal condition is the basis of the dose calculation in clinical practice. My objective is to study and apply a heterogenic temperature pattern during the heating process [...] Read more.

(1) Background: Hyperthermia in oncology conventionally seeks the homogeneous heating of the tumor mass. The expected isothermal condition is the basis of the dose calculation in clinical practice. My objective is to study and apply a heterogenic temperature pattern during the heating process and show how it supports radiotherapy. (2) Methods: The targeted tissue’s natural electric and thermal heterogeneity is used for the selective heating of the cancer cells. The amplitude-modulated radiofrequency current focuses the energy absorption on the membrane rafts of the malignant cells. The energy partly “nonthermally” excites and partly heats the absorbing protein complexes. (3) Results: The excitation of the transmembrane proteins induces an extrinsic caspase-dependent apoptotic pathway, while the heat stress promotes the intrinsic caspase-dependent and independent apoptotic signals generated by mitochondria. The molecular changes synergize the method with radiotherapy and promote the abscopal effect. The mild average temperature (39–41 °C) intensifies the blood flow for promoting oxygenation in combination with radiotherapy. The preclinical experiences verify, and the clinical studies validate the method. (4) Conclusions: The heterogenic, molecular targeting has similarities with DNA strand-breaking in radiotherapy. The controlled energy absorption allows using a similar energy dose to radiotherapy (J/kg). The two therapies are synergistically combined. Full article

(This article belongs to the Special Issue Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation)

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57 pages, 2143 KiB

Open AccessEditor’s ChoiceReview

Clinical Evidence for Thermometric Parameters to Guide Hyperthermia Treatment

by Adela Ademaj, Danai P. Veltsista, Pirus Ghadjar, Dietmar Marder, Eva Oberacker, Oliver J. Ott, Peter Wust, Emsad Puric, Roger A. Hälg, Susanne Rogers, Stephan Bodis, Rainer Fietkau, Hans Crezee and Oliver Riesterer

Cancers 2022, 14(3), 625; https://doi.org/10.3390/cancers14030625 - 26 Jan 2022

Cited by 19 | Viewed by 4497

Abstract

Hyperthermia (HT) is a cancer treatment modality which targets malignant tissues by heating to 40–43 °C. In addition to its direct antitumor effects, HT potently sensitizes the tumor to radiotherapy (RT) and chemotherapy (CT), thereby enabling complete eradication of some tumor entities as [...] Read more.

Hyperthermia (HT) is a cancer treatment modality which targets malignant tissues by heating to 40–43 °C. In addition to its direct antitumor effects, HT potently sensitizes the tumor to radiotherapy (RT) and chemotherapy (CT), thereby enabling complete eradication of some tumor entities as shown in randomized clinical trials. Despite the proven efficacy of HT in combination with classic cancer treatments, there are limited international standards for the delivery of HT in the clinical setting. Consequently, there is a large variability in reported data on thermometric parameters, including the temperature obtained from multiple reference points, heating duration, thermal dose, time interval, and sequence between HT and other treatment modalities. Evidence from some clinical trials indicates that thermal dose, which correlates with heating time and temperature achieved, could be used as a predictive marker for treatment efficacy in future studies. Similarly, other thermometric parameters when chosen optimally are associated with increased antitumor efficacy. This review summarizes the existing clinical evidence for the prognostic and predictive role of the most important thermometric parameters to guide the combined treatment of RT and CT with HT. In conclusion, we call for the standardization of thermometric parameters and stress the importance for their validation in future prospective clinical studies. Full article

(This article belongs to the Special Issue Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation)

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Hyperthermia: A Potential Game-Changer in the Management of Cancers in Low-Middle-Income Group Countries

by Niloy R. Datta, Bharati M. Jain, Zatin Mathi, Sneha Datta, Satyendra Johari, Ashok R. Singh, Pallavi Kalbande, Pournima Kale, Vitaladevuni Shivkumar and Stephan Bodis

Cancers 2022, 14(2), 315; https://doi.org/10.3390/cancers14020315 - 9 Jan 2022

Cited by 18 | Viewed by 3308

Abstract

Loco-regional hyperthermia at 40–44 °C is a multifaceted therapeutic modality with the distinct triple advantage of being a potent radiosensitizer, a chemosensitizer and an immunomodulator. Risk difference estimates from pairwise meta-analysis have shown that the local tumour control could be improved by 22.3% [...] Read more.

Loco-regional hyperthermia at 40–44 °C is a multifaceted therapeutic modality with the distinct triple advantage of being a potent radiosensitizer, a chemosensitizer and an immunomodulator. Risk difference estimates from pairwise meta-analysis have shown that the local tumour control could be improved by 22.3% (p < 0.001), 22.1% (p < 0.001) and 25.5% (p < 0.001) in recurrent breast cancers, locally advanced cervix cancer (LACC) and locally advanced head and neck cancers, respectively by adding hyperthermia to radiotherapy over radiotherapy alone. Furthermore, thermochemoradiotherapy in LACC have shown to reduce the local failure rates by 10.1% (p = 0.03) and decrease deaths by 5.6% (95% CI: 0.6–11.8%) over chemoradiotherapy alone. As around one-third of the cancer cases in low-middle-income group countries belong to breast, cervix and head and neck regions, hyperthermia could be a potential game-changer and expected to augment the clinical outcomes of these patients in conjunction with radiotherapy and/or chemotherapy. Further, hyperthermia could also be a cost-effective therapeutic modality as the capital costs for setting up a hyperthermia facility is relatively low. Thus, the positive outcomes evident from various phase III randomized trials and meta-analysis with thermoradiotherapy or thermochemoradiotherapy justifies the integration of hyperthermia in the therapeutic armamentarium of clinical management of cancer, especially in low-middle-income group countries. Full article

(This article belongs to the Special Issue Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation)

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