Thermal Isoeffect Dose Research Articles

Outcomes of CEM43 in Predicting Thermal Damage Induced by Focal Laser Ablation in Controlled Ex Vivo Experiments: A Comparison to Histology and MRI.

Focal laser ablation (FLA) serves as a targeted therapy for prostate cancer (PCa). Clinical studies have demonstrated significant variations in ablation volumes with consistent fiber configurations. Consequently, a prediction model is needed for the safe application of FLA in treating PCa. This study aimed to evaluate the reproducibility of FLA-induced temperature profiles in controlled ex vivo experiments using clinical laser treatment protocols. Additionally, it sought to examine the effectiveness of the CEM43 model in predicting the zone of irreversible damage (ZID) and to compare these findings with outcomes derived from the Arrhenius model. Freshly excised postmortem human prostate and porcine liver specimens were used for controlled ex vivo ablation. Tissues were secured in a Perspex sample holder for precise placement of the laser fiber and thermocouples. FLA was conducted with a 1064-nm Nd:YAG laser at 3 W in continuous-wave mode for 10 min. Pre- and post-FLA 3D T1-weighted 7 T MRI scans were obtained to assess the treatment area. Whole-mount hematoxylin and eosin histological slides were prepared and digitized. On histology, the ZID was defined as the total of vaporized, carbonized, and coagulated tissue. A 2D thermal development map was created from temperature data, using bi-cubic interpolation. The cumulative equivalent thermal isoeffect dose at 43°C in minutes (CEM43) model was applied to predict the ZID, with 240 equivalent minutes (240-CEM43) used as the damage threshold. Additionally, the Arrhenius thermal model was used for comparison of CEM43 results. Predicted ZIDs were compared to MRI and histology. FLA treatment was performed on ex vivo human prostate samples (n = 2) and porcine liver specimens (n = 5). For human prostate tissue, FLA did not result in an identifiable ZID upon histological macroscopic examination or a lesion on MRI. Ex vivo porcine liver samples showed a clearly demarcated oval-shaped hyperintense lesion surrounding the laser fiber tip on post-FLA MRI. The MRI lesion (range 1.6-2.1 cm2) corresponded with the shape and location of the ZID on histology, but was smaller (median 1.7 vs. 3.2, p = 0.02). Histological examination of porcine liver samples revealed ZIDs ranging from 2.1 to 4.1 cm2, whereas 240-CEM43-predicted ZIDs ranged from 3.3 to 3.8 cm2. Although the median 240-CEM43-predicted ZID was not significantly larger than the histology ZID (3.8 vs. 3.2 cm2, p = 0.22), it tended to overpredict the histological results in most experiments. The median Arrhenius-predicted ZID was similar to the histologicalZID (3.2 vs. 3.2 cm2, p = 0.56), but varied in size when comparing individual experiments (range 2.5-3.2 cm2). FLA on ex vivo human prostate showed no thermal damage on histopathology or MRI. Ex vivo porcine liver FLA resulted in identifiable ZID on histology and lesions on MRI. 240-CEM43 generally overestimated the ZID and had less variability compared to histology. Results from the Arrhenius model were in better agreement with the histology findings, but still did not predict the individual FLA-induced histological thermal damage. Inter-experiment ZID variability underlines the need for developing a more comprehensive predictive dosimetry model for FLA in PCa treatment.

Lesion 3D modeling in transcranial MR-guided focused ultrasound thalamotomy

Transcranial magnetic resonance-guided focused ultrasound (tMRgFUS) allows to perform incisionless thermoablation of deep brain structures. This feature makes it a very useful tool for the treatment of multiple neurological and psychiatric disorders. Currently, feedback of the thermoablation process is based on peak temperature readings assessed on real-time two-dimensional MRI thermometry. However, an accurate methodology relating thermal dosimetry with three-dimensional topography and temporal evolution of the lesion is still to be defined, thus hurdling the establishment of well-defined, evidence-based criteria to perform safe and effective treatments. In here we propose threshold-based thermoablation models to predict the volumetric topography of the lesion (whole lesion and necrotic core) in the short-to-mid-term based on thermal dosimetry estimated from intra-treatment MRI thermometry. To define and validate our models we retrospectively analyzed the data of sixty-three tMRgFUS thalamotomies for treating tremor. We used intra-treatment MRI thermometry to estimate whole-treatment three-dimensional thermal dose maps, defined either as peak temperature reached (Tmax) or thermal isoeffective dose (TID). Those maps were thresholded to find the dosimetric level that maximize the agreement (Sorensen-Dice coefficient - SDc) with the boundaries of the whole lesion and its core, assessed on T2w images 1-day (post-24h) and 3-months (post-3M) after treatment. Best predictions were achieved for the whole lesion at post-24h (SDc = 0.71), with Tmax /TID over 50.0 °C/90.5 CEM43. The core at post-24h and whole lesion at post-3M lesions reported a similar behavior in terms of shape accuracy (SDc ~0.35), and thermal dose thresholds ~55 °C/4100.0 CEM43. Finally, the optimal levels for post-3M core lesions were 55.5 °C/5800.0 CEM43 (SDc = 0.21). These thermoablation models could contribute to the real-time decision-making process and improve the outcome of tMRgFUS interventions both in terms of safety and efficacy.

Thermal dose as a universal tool to evaluate nanoparticle-induced photothermal therapy.

Thermal isoeffect dose (TID) is a widely applied concept to evaluate the safety of medical devices that can expose patients to heat. However, it has rarely been used in photothermal therapy (PTT), where nanoparticles are used as light absorbers. Utilizing TID in an appropriate way would make it feasible to compare the results obtained with different light absorbers as well as clarifying their cellular effects. Herein, we apply TID as a definitive parameter to evaluate the outcomes of a nanoparticle-induced PTT in vitro. We show that cell death measured with an ATP-based viability assay and flow cytometry can be correlated with TID if time-temperature data is available. As an experimental model, black porous silicon nanoparticles were studied as photothermal agents to kill HeLa cancer cells. The results indicate that as the critical TID of 70min is reached, the cells start to undergo apoptosis independently of the way in which the TID was attained: by long heating at low temperatures or by short heating at high temperatures. Overall, TID is proposed as a valid parameter which could be determined in the PTT studies to allow a straightforward comparison of the published results and the elucidation of the cell death mechanisms.

Broadband Dielectric Properties of Ex Vivo Bovine Liver Tissue Characterized at Ablative Temperatures

To investigate the thermal and frequency dependence of dielectric properties of ex vivo liver tissue - relative permittivity and effective conductivity - over the frequency range 500 MHz to 6GHz and temperatures ranging from 20 to 130°C. We measured the dielectric properties of fresh ex vivo bovine liver tissue using the open-ended coaxial probe method (n = 15 samples). Numerical optimization techniques were utilized to obtain parametric models for characterizing changes in broadband dielectric properties as a function of temperature and thermal isoeffective dose. The effect of heating tissue at rates over the range 6.4-16.9°C/min was studied. The measured dielectric properties were used in simulations of microwave ablation to assess changes in simulated antenna return loss compared to experimental measurements. Across all frequencies, both relative permittivity and effective conductivity dropped sharply over the temperature range 89 - 107°C. Below 91°C, the slope of the effective conductivity changes from positive values at lower frequencies (0.5-1.64GHz) to negative values at higher frequencies (1.64-6GHz). The maximum achieved correlation values between transient reflection coefficients from measurements and simulations ranged between 0.83 - 0.89 and 0.68 - 0.91, respectively, when using temperature-dependent and thermal-dose dependent dielectric property parameterizations. We have presented experimental measurements and parametric models for characterizing changes in dielectric properties of bovine liver tissue at ablative temperatures. The presented dielectric property models will contribute to the development of ablation systems operating at frequencies other than 2.45GHz, as well as broadband techniques for monitoring growth of microwave ablation zones.

HYPERTHERMIA EFFECT ON HUMAN NORMAL BREAST (MCF-10A) AND CANCER (MDA-MB 231 AND MCF-7) CELLS

Objective: In this study, the hyperthermia effect on the viability of human normal breast (MCF-10A) and cancer (MDA-MB 231 and MCF-7) cells was evaluated by MTT assay.
 Methods: Cells were exposed to heat at 38ºC, 39ºC, 40ºC, 41ºC, 42ºC, 43ºC, and 44ºC for five different durations of heat exposure (0.5, 1, 2, 3, and 4 h). Breakpoint temperatures of MCF-10A, MDA-MB 231, and MCF-7 were determined using cumulative equivalent 43°C (CEM43) model. This model was first time used to calculate thermal isoeffect dose (TID) for MCF-10A, MDA-MB 231, and MCF-7.
 Results: MCF-10A started to die at 42°C for 3 h while MDA-MB 231 and MCF-7 need a temperature of 38°C for 0.5 h; thus, they were identified as the threshold temperatures in CEM43 model. Furthermore, the effect of “43°C incubator 2 h” had similar total thermal dose as “44°C incubator 0.5 h” for MDA-MB 231 and MCF-7. In addition, “43°C incubator 3 h” effect had also almost the same thermal dose as “44°C incubator 1 h” for MDA-MB 231 and MCF-7.
 Conclusion: A better understanding of the significant correlations between CEM43 and response parameters in clinical trials could be useful to treat breast cancer patients.

‘Relationship between thermal dose and cell death for “rapid” ablative and “slow” hyperthermic heating’

Aim: Thermal isoeffective dose (TID) has not been convincingly validated for application to predict biological effects from rapid thermal ablation (e.g., using >55 °C). This study compares the classical method of quantifying TID (derived from hyperthermia data) with a temperature-adjusted method based on the Arrhenius model for predicting cell survival in vitro, after either ‘rapid’ ablative or ‘slow’ hyperthermic exposures.Methods: MTT assay viability data was obtained from two human colon cancer cell lines, (HCT116, HT29), subjected to a range of TIDs (120–720 CEM43) using a thermal cycler for hyperthermic (>2 minutes, <50 °C) treatments, or a novel pre-heated water bath based technique for ablative exposures (<10 seconds, >55 °C). TID was initially estimated using a constant RCEM>43°C=0.5, and subsequently using RCEM(T), derived from temperature dependent cell survival (injury rate) Arrhenius analysis.Results: ‘Slow’ and ‘rapid’ exposures resulted in cell survival and significant regrowth (both cell lines) 10 days post-treatment for 240 CEM43 (RCEM>43°C=0.5), while 340-550 CEM43 (RCEM>43°C =0.5) delivered using ‘rapid’ exposures showed 12 ± 6% viability and ‘slow’ exposures resulted in undetectable viability. Arrhenius analysis of experimental data (activation energy ΔE = 5.78 ± 0.04 × 105 J mole−1, frequency factor A = 3.27 ± 11 × 1091 sec−1) yielded RCEM=0.42 * e0.0041*T which better-predicted cell survival than using R CEM> 43°C=0.5.Conclusions: TID calculated using an RCEM(T) informed by Arrhenius kinetic parameters provided a more consistent, heating strategy independent, predictor of cell viability, improving dosimetry of ablative thermal exposures. Cell viability was only undetectable above 305 ± 10 CEM43 using this revised measure.

Cytotoxicity of hepatocellular carcinoma cells to hyperthermic and ablative temperature exposures: In vitro studies and mathematical modelling

Purpose: Image-guided ablative therapies use temperatures greater than 45 °C to kill abnormal cells. There is limited published data of cell survival after ablative temperature exposures, which is of importance to predict ablation zone dimensions. The objective of this study was to determine and mathematically model survival of hepatocellular carcinoma cells following ablative temperature exposures (45–60 °C).Materials and methods: Hepatocellular carcinoma (HCC) cell lines were plated in 96-well plates, and heated between 45 and 60 °C for 0–32 min. Heating was applied by a rapid media exchange with heated Hank’s balanced salt solution (HBSS) in a temperature-controlled water bath. Cell viability was determined by MTS assay. Survival data was modelled by the Arrhenius model, and the thermal isoeffective dose (TID) model where kinetic parameters were determined via non-linear optimisation.Results: Results suggest that the thermal dose based on cumulative equivalent minutes and parameters as used for hyperthermia exposures (<43 °C) is not applicable for ablative exposures. We found R = 0.72 for temperatures between 45–60°C for the TID model. The Arrhenius parameters were frequency factor A = 3.25E43 1/s, and activation energy Ea = 281 kJ/mol. These parameters correlate well with a prior study in the same cell line, and with threshold temperatures for necrosis from in vivo studies.Conclusions: Our results suggest that standard TID model kinetic parameters based on hyperthermia studies, often also used at ablation temperatures, are not applicable at these higher temperatures for HCC cells.

Mathematical models of laser-induced tissue thermal damage

Laser sources are under increasing study for in vivo tumour ablation. Photo-thermal ablation in tissues varies tremendously in governing physical phenomena, depending on wavelength, owing to wide variation in the optical properties of tissues, specifically the dominant chromophore and degree and type of scattering. Once converted into local tissue heating, however, the governing thermodynamic principles remain the same. Observed irreversible thermal alterations range from substantial structural disruption due to steam evolution in high temperature short-term activations to low temperature rise, longer-term initiation of the complex protein cascades that result in apoptosis and/or necroptosis. The usual mathematical model in hyperthermia studies, the thermal isoeffect dose, arising from the relative reaction rate formulation, is not an effective description of the higher temperature effects because multiple processes occur in parallel. The Arrhenius formulation based on the theory of absolute reaction rates is much more useful and descriptive in laser heating since the multiple thermodynamically independent processes may be studied separately.

Improved power steering with double and triple ring waveguide systems: The impact of the operating frequency

Introduction: Regional hyperthermia systems with 3D power steering have been introduced to improve tumour temperatures. The 3D 70-MHz AMC-8 system has two rings of four waveguides. The aim of this study is to evaluate whether T90 will improve by using a higher operating frequency and whether further improvement is possible by adding a third ring.Methods: Optimised specific absorption rate (SAR) distributions were evaluated for a centrally located target in tissue-equivalent phantoms, and temperature optimisation was performed for five cervical carcinoma patients with constraints to normal tissue temperatures. The resulting T90 and the thermal iso-effect dose (i.e. the number of equivalent min at 43°C) were evaluated and compared to the 2D 70-MHz AMC-4 system with a single ring of four waveguides. FDTD simulations were performed at 2.5 × 2.5 × 5 mm3 resolution. The applied frequencies were 70, 100, 120, 130, 140 and 150 MHz.Results: Optimised SAR distributions in phantoms showed an optimal SAR distribution at 140 MHz. For the patient simulations, an optimal increase in T90 was observed at 130 MHz. For a two-ring system at 70 MHz the gain in T90 was about 0.5°C compared to the AMC-4 system, averaged over the five patients. At 130 MHz the average gain in T90 was ∼1.5°C and ∼2°C for a two and three-ring system, respectively. This implies an improvement of the thermal iso-effect dose with a factor ∼12 and ∼30, respectively.Conclusion: Simulations showed that a 130-MHz two-ring waveguide system yields significantly higher tumour temperatures compared to 70-MHz single-ring and double-ring waveguide systems. Temperatures were further improved with a 130-MHz triple-ring system.

Models for Thermal Damage in Tissues: Processes and Applications

Irreversible thermal alterations in tissue function and structure are used in clinical applications to achieve diverse goals, from lower-temperature tumor ablation to higher-temperature tissue fusion and surgical cutting. The typical formulation in tumor hyperthermia studies, the thermal iso-effect dose, derives from cell-survival studies but describes a single process only over a limited range of temperatures and is thus not suitable for multiple higher-temperature events. Many other thermal damage processes have been described using the Arrhenius kinetic rate of formation approach, which has the advantage that it is inherently quantitative in nature and can easily be compared with quantitative markers of injury or histologic section. The vast majority of Arrhenius studies have been directed toward measurable cellular effects at relatively low temperatures. Some emphasis in this paper has been placed on what is known of higher-temperature processes to support the theme of this issue. This review compares and contrasts the two thermal-damage formulations and reviews methods to convert between them.

Thermal Therapy in Urologic Systems: A Comparison of Arrhenius and Thermal Isoeffective Dose Models in Predicting Hyperthermic Injury

The Arrhenius and thermal isoeffective dose (TID) models are the two most commonly used models for predicting hyperthermic injury. The TID model is essentially derived from the Arrhenius model, but due to a variety of assumptions and simplifications now leads to different predictions, particularly at temperatures higher than 50 degrees C. In the present study, the two models are compared and their appropriateness tested for predicting hyperthermic injury in both the traditional hyperthermia (usually, 43-50 degrees C) and thermal surgery (or thermal therapy/thermal ablation, usually, >50 degrees C) regime. The kinetic parameters of thermal injury in both models were obtained from the literature (or literature data), tabulated, and analyzed for various prostate and kidney systems. It was found that the kinetic parameters vary widely, and were particularly dependent on the cell or tissue type, injury assay used, and the time when the injury assessment was performed. In order to compare the capability of the two models for thermal injury prediction, thermal thresholds for complete killing (i.e., 99% cell or tissue injury) were predicted using the models in two important urologic systems, viz., the benign prostatic hyperplasia tissue and the normal porcine kidney tissue. The predictions of the two models matched well at temperatures below 50 degrees C. At higher temperatures, however, the thermal thresholds predicted using the TID model with a constant R value of 0.5, the value commonly used in the traditional hyperthermia literature, are much lower than those predicted using the Arrhenius model. This suggests that traditional use of the TID model (i.e., R=0.5) is inappropriate for predicting hyperthermic injury in the thermal surgery regime (>50 degrees C). Finally, the time-temperature relationships for complete killing (i.e., 99% injury) were calculated and analyzed using the Arrhenius model for the various prostate and kidney systems.

Arrhenius relationships from the molecule and cell to the clinic

There are great differences in heat sensitivity between different cell types and tissues. However, for an isoeffect induced in a specific cell type or tissue by heating for different durations at different temperatures varying from 43–44°C up to about 57°C, the duration of heating must be increased by a factor of about 2 (R value) when the temperature is decreased by 1°C. This same time–temperature relationship has been observed for heat inactivation of proteins, and changing only one amino acid out of 253 can shift the temperature for a given amount of protein denaturation from 46°C to either 43 or 49°C. For cytotoxic temperatures <43–44°C, R for mammalian cells and tissues is about 4–6. Many factors change the absolute heat sensitivity of mammalian cells by about 1°C, but these factors have little effect on Rs, although the transition in R at 43–44°C may be eliminated or shifted by about 1°C. R for heat radiosensitization are similar to those above for heat cytotoxicity, but Rs for heat chemosensitization are much smaller (usually about 1.1–1.2). In practically all of the clinical trials that have been conducted, heat and radiation have been separated by 30–60 min, for which the primary effect should be heat cytotoxicity and not heat radiosensitization. Data are presented showing the clinical application of the thermal isoeffect dose (TID) concept in which different heating protocols for different times at different temperatures are converted into equivalent minutes (equiv) min at 43°C (EM43). For several heat treatments in the clinic, the TIDs for each treatment can be added to give a cumulative equiv min at 43°C, namely, CEM43. This TID concept was applied by Oleson et al. in a retrospective analysis of clinical data, with the intent of using this approach prospectively to guide future clinical studies. Considerations of laboratory data and the large variations in temperature distributions observed in human tumors indicate that thermal tolerance, which has been observed for mammalian cells for both heat killing and heat radiosensitization, probably is not very important in the clinic. However, if thermal tolerance did occur in the clinical trials in which fractionation schemes were varied, it probably would not have been detected because with only the two–three-fold change in treatment time that occurs when comparing one versus two fractions per week, or three versus six total fractions, little difference would be expected in the response of the tumors since both thermal doses were extremely low on the dose-response curve. Data are shown which indicate that in order to test for thermal tolerance in the clinic and to have a successful phase III trial, the thermal dose should be increased about five-fold compared with what has been achieved in previous clinical trials. This increase in thermal dose could be achieved by increasing the temperature about 1.5°C (from 39.5 to 41.0°C in 90% of the tumor) or by increasing the total treatment time about five-fold. The estimate is that 90% of the tumor should receive a cumulative thermal dose (CEM43) of at least 25; this is abbreviated as a CEM43 T90 of 25. This value of 25 compares with 5 observed by Oleson et al. in their soft tissue sarcoma study. Arguments also are presented that thermal doses much higher than the CEM43 T90 induce the hyperthermic damage that causes the tumors to respond, and that the minimum CEM43 T90 of 25 only predicts which tumors that receive a certain minimal thermal dose in <90% of the regions of the tumors will respond. For example, in addition to a minimal CEM43 T90 of 25 a minimum CEM43 T50 of about 400 also may be required for a response. Finally, continuous heating for ∼2 days at about 41°C during either interstitial low dose-rate irradiation or fractionated high dose-rate irradiation, which we estimate could give a CEM43 of 75, should be considered in order to enhance heat radiosensitization of the tumor as well as heat cytotoxicity. In order to exploit the use of hyperthermia in the clinic, we need a better understanding of the biology and physiology of heat effects in tumors and various normal tissues. As an example of an approach for mechanistic studies, one specific study is described which demonstrates that damage to the centrosome of CHO cells heated during G1 causes irregular divisions that result in multinucleated cells that do not continue dividing to form colonies. This may or may not be relevant for heat damage in vivo. However, since normal tissues vary in thermal sensitivity by a factor of 10, similar approaches are needed to describe the fundamental lethal events that occur in the cells comprising the different tissues.

Whole-body hyperthermia with water-filtered infrared radiation: technical-physical aspects and clinical experiences

Among the different methods of whole-body hyperthermia (WBH), the energy transfer with infrared radiation seems to have established itself as a relatively simple procedure. The infrared systems differ with regard to the used spectrum of radiation. In the case of water-filtered infrared radiation, infrared A (760-1400 nm) is the focal point of heat radiation. This radiation penetrates deep into the skin up to the capillary area of the corium. Eighty treatments of patients in an advanced stage of cancer (40 male, 40 female, April 1998-April 1999) were performed with a WBH device with water-filtered infrared radiation, IRATHERM 2000. Extreme WBH was combined with induced hyperglycaemia and relative hyperoxaemia, and for 83% of the patients with chemotherapy as well. The body-core temperature was measured rectally (85%) or vesically. The objectives of the thermal control were a low rate of side-effects and a quick rise of the body-core temperature with regard to the condition of the patient's skin. The mean duration of the rising phase (37.5-41.5 degrees C) was 87 +/- 19 min. A correlation between lamp power and rising time (r = 0.08) was not found. Moreover, no correlation could be found between the appearance of thermal lesions > or = WHO 2nd degree and the lamp power. Thermal lesions according to WHO 1st, 2nd and 3rd degrees appeared in the case of 20, 15 and one treatment, respectively. Their area amounted in 2nd-degree cases to 0.08% of the body surface, on average. The highest mean temperature over 60 min (T60) was 42.1 +/- 0.1 degrees C, and the mean of maximum temperature (Tmax) was 42.3 +/- 0.1 degrees C. The mean thermal isoeffect dose EM43 was 35.8 +/- 6.3 min. WBH with water-filtered infrared radiation in combination with induced hyperglycaemia and relative hyperoxaemia (procedure of systemic Cancer Multistep Therapy) is a safe and practicable procedure with good tolerability in the case of experienced application. It permits a rapid rise of body-core temperature and a high thermal constancy in the plateau phase. An all-around access to the patient is possible in all therapy phases.

A new model of thermal inactivation and its application to clonogenic survival data for WiDr human colonic adenocarcinoma cells.

Based on the analysis of clonogenic survival data for human colonic adenocarcinoma cells (WiDr) after a single heating, a new model is proposed to describe cell survival after hyperthermia quantitatively. The effects of heat are explained as heat-induced cell damage assuming a first-order (single-hit) and a second-order (cumulative damage) process. Thus cell survival at a specified temperature can be described by the linear-quadratic (LQ) model. The proposed model is based on an alternative definition of the (single) thermal dose, given as the (normalized) product of heating time and a specified nonlinear function of the increase in temperature (relative to a threshold temperature) to be interpreted as the thermal dose rate. In further analogy to the modeling of the effects of low-dose-rate radiation, an inherent capacity of the cells to repair sublethal damage is assumed, and these effects are quantified by the usual g factor measuring incomplete repair effects. The model defines thermal dose-response and isoeffect dose relationships, enabling a direct (i. e. single-step) analysis of the available thermal response data. Additionally, the analysis of our data based on heating times in the range from 0 to 360 min and temperatures from 41 to 46 degrees C and covering a broad spectrum of different densities of cells seeded for colony formation did not yield any evidence of the existence of a breaking point usually derived from Arrhenius plots based on the single-hit, multitarget model and the Arrhenius equation. The model includes no specific assumptions describing the development of thermotolerance, which can be assumed to be negligible under our experimental conditions. The proposed thermal dose-response model correlates satisfactorily with the in vitro survival data for WiDr adenocarcinoma cells.

Venovenous perfusion-induced systemic hyperthermia: hemodynamics, blood flow, and thermal gradients

Background. Thermal events during extracorporeal venovenous perfusion-induced systemic hyperthermia (VV-PISH) were studied and related to determination of whole-body and regional thermal isoeffect doses. Methods. Swine ( n=6, 77 ± 4.5 kg) were heated to a target temperature of 43°C for 120 minutes using VV-PISH. Colored microspheres were injected during preheat, heat induction, maintenance, cool down, and after decannulation. The esophageal, tympanic, rectal, pulmonary artery, bladder, bone marrow, kidney, brain, blood, lung, and airway temperatures were recorded continuously. The thermal dose, thermal exchange, metabolic heat production, heat loss to the environment, the change in body heat, and the thermal isoeffect dose were studied at 15-minute intervals. Results. VV-PISH increased heart rate and cardiac output and caused a redistribution of blood flow favoring the thoracoabdominal organs. Greatest thermal exchange occurred during the heating phase (total 2,162 ± 143 kJ), metabolic heat production contributed in all phases (274 ± 9 kJ), the greatest change in body heat occurred during heating (1,310 ± 309 kJ) with a total delivered thermal dose of 298 ± 21 kJ, and the total whole body thermal isoeffect dose at 100 ± 5 minutes. Conclusions. VV-PISH is feasible, is capable of transferring sufficient heat, causes a redistribution of blood flow favoring the thoracoabdominal organs, and facilitates calculation of whole-body and regional thermal isoeffect doses.

Arrhenius analysis of the thermal response of human colonic adenocarcinoma cells in vitro using the multi-target, single-hit and the linear-quadratic model

In order to compare the intrinsic thermal sensitivity of different malignant cell lines the multi-target, single-hit model has been widely accepted. It is even applied in clinical hyperthermia by the so-called thermal isoeffect dose (TID) concept originated from this model. The second model which is preferentially used to describe radiation survival curves is the linear-quadratic (LQ) model which can be also applied to thermal response. Interestingly, no breaking point and different activation energies are obtained with this model. In the present paper we demonstrate this discrepancy with the two human colonic adenocarcinoma cell lines WiDr and SW620. Our results further validate the already earlier published persuasion, that neither the multi-target, single-hit model, nor the LQ model are adequate to describe hyperthermic survival. Since both models give completely different results, further data aquisition of isoeffect factors, breaking points and activation enthalpies based on the multi-target, single-hit model only, is unprofitable until advanced models of thermal inactivation have been developed.

Analysis of thermal parameters obtained during Phase III trials of hyperthermia as an adjunct to radiotherapy in the treatment of breast carcinoma

An analysis of 351 HT treatment sessions administered to 101 patients receiving radiotherapy and hyperthermia (RT + HT) who were entered into Phase III concurrent randomized trials for recurrent (BrR) and intact (BrI) breast tumours is presented. A complete response (CR) was recorded in 50 of 84 (595%) fields in the case of recurrent breast patients and in 10 of 17 (59%) fields in the case of the intact breast patients. In comparison, 15 of 60 (25%) patients entered into BrR who received RT alone and 8 of 12 (667%) patients receiving RT alone entered into BrI trial achieved CR. A set ot thermal parameters is defined and evaluated on a treatment by treatment basis. Patient and tumour characteristics influential on CR are identified and thermal parameters which have additional prognostic value are investigated. Multivariate logistic analysis of the non-thermal data showed that maximum depth of tumour, presence or history of disease outside the treated area and RT regimen were most influential on CR. Tumour volume (cm3) (OR = 0.996, 95% CI = 0.993-1 0004, p = 008) was not a strong prognostic covariate; tumour area and linear dimensions were even less significant (p = 0.41). The cumulative minimum thermal isoeffect dose (equivalent minutes at 43°C) accrued over the 1st, 1st and 2nd, and 1st, 2nd and 3rd treatment sessions was the only thermal parameter to exhibit an association with CR consistently. Other thermal parameters found to contribute to the predictive models were MINTIME > 42°C calculated for the 1st treatment session and %sensors > 43°C (peak) calculated for the 2nd treatment session.

Arrhenius relationships from the molecule and cell to the clinic.

There are great differences in heat sensitivity between different cell types and tissues. However, for an isoeffefct induced in a specific cell type or tissue by heating for different durations at different temperatures varying from 43-44 degrees C up to about 57 degrees C, the duration of heating must be increased by a factor of about 2 (R value) when the temperature is decreased by 1 degrees C. This same time-temperature relationship has been observed for heat inactivation of proteins, and changing only one amino acid out of 253 can shift the temperature for a given amount of protein denaturation from 46 degrees C to either 43 or 49 degrees C. For cytotoxic temperatures < 43-44 degrees C, R for mammalian cells and tissues is about 4-6. Many factors change the absolute heat sensitivity of mammalian cells by about 1 degrees C, but these factors have little effect on Rs, although the transition in R at 43-44 degrees C may be eliminated or shifted by about 1 degrees C. R for heat radiosensitization are similar to those above for heat cytotoxicity, but Rs for heat chemosensitization are much smaller (usually about 1.1-1.2). In practically all of the clinical trials that have been conducted, heat and radiation have been separated by 30-60 min, for which the primary effect should be heat cytotoxicity and not heat radiosensitization. Data are presented showing the clinical application of the thermal isoeffect dose (TID) concept in which different heating protocols for different times at different temperatures are converted into equiv min at 43 degrees C (EM43). For several heat treatments in the clinic, the TIDs for each treatment can be added to give a cumulative equiv min at 43 degrees C, viz., CEM43. This TID concept was applied by Oleson et al. in a retrospective analysis of clinical data, with the intent of using this approach prospectively to guide future clinical studies. Considerations of laboratory data and the large variations in temperature distributions observed in human tumours indicate that thermal tolerance, which has been observed for mammalian cells for both heat killing and heat radiosensitization, probably is not very important in the clinic.(ABSTRACT TRUNCATED AT 400 WORDS)

Evaluation of 45°C Hyperthermia and Irradiation

This report describes biologic experiments using transplanted RIF-1 tumors (diameter 0.5 or 1 cm) in C3H/He inbred mice (12 to 20 per treatment group) to compare the results with heat alone (43 degrees C for 60 minutes or 45 degrees C for 15 minutes, twice weekly via radiofrequency electrodes), irradiation alone (400 cGy twice weekly for a total of 4,000 cGy with 140 kVp x-rays), or a combination of both therapies. Animals receiving combined treatment had significantly greater complete regression than those treated with either therapy alone. Tumor regrowth curves were equivalent for 43 degrees C or 45 degrees C following irradiation. In tumors 0.5 cm in diameter the overall tumor cure rates were 17% for 43 degrees C for 60 minutes and 25% for 45 degrees C for 15 minutes with heat alone and 8% with irradiation alone; the combination of irradiation and heat at both temperatures yielded comparable complete cure rates (75 and 67%). With 1-cm tumors the corresponding cure rates were 0% with heat alone (either temperature), 5% for irradiation alone, 33% for irradiation and 43 degrees C heat, and 64% for irradiation and 45 degrees C heat (p = .3). Approximately 20% of the animals in the various groups developed moist or dry desquamation in the area treated, whereas 40 to 66% exhibited moist desquamation. There was a slight increase in this sequela (73%) for mice that received irradiation and 45 degrees C compared with 50% in mice treated with 43 degrees C, but the difference was not statistically different (p = .54). Experimental studies demonstrated equivalent efficacy of 10 hyperthermia sessions at 43 degrees C or 45 degrees C combined with irradiation. Caution must be exercised in the clinical application of thermal iso-effect heat dose concepts until further clinical trials have been performed and there is a better understanding of the time-temperature relationship.

Sensitivity of hyperthermia trial outcomes to temperature and time: Implications for thermal goals of treatment

Purpose : In previous work we have found that the cumulative minutes of treatment for which 90% of measured intratumoral temperatures (T 90) exceeded 39.5°C was highly associated with complete response of superficial tumors. Similarly, the cumulative time for which 50% of intratumoral temperatures (T 50) exceeded 41.5°C was highly associated with the presence of > 80% necrosis in soft tissue sarcomas resected after radiotherapy and hyperthermia. In the present work we have calculated the time for isoeffective treatments with T 90 = 43°C and T 50 = 43°C, respectively, using published thermal isoeffective dose formulae. The purpose of these calculations was to determine the sensitivity of treatment outcome to variations in thermal isoeffective dose. Methods and Materials : The basis for the calculations were the thermal parameters and treatment outcomes in three patient populations: 44 patients with moderate or high grade soft tissue sarcoma treated preoperatively with hyperthermia and radiation; 105 patients with superficial tumors treated with hyperthermia and radiation, and 59 patients with deep tumors treated with hyperthermia and radiation. Results : The thermal dose values calculated are strongly associated with outcome in multivariate logistic regression analysis. Simple dose-response equations result from the analysis, and we use these equations to assess the sensitivity of outcome upon variations in thermal dose. This information, in turn, allows us to estimate the number of patients required in Phase II and III trials of hyperthermia and radiation therapy. Conclusions : For regimens of 5 to 10 hyperthermia treatments, improvements in median T 90 (superficial tumors) and T 50 (deep tumors) parameters by 1.2 – 1.5°C could result in response rates high enough (compared to radiotherapy alone) to justify Phase III trials. A similar improvement in response rates would require an increase in overall duration of treatment by a factor of 3 to 5. This would be difficult to achieve while also avoiding thermal tolerance induction. Achieving these temperature goals may be possible with improvements in hyperthermia technology. Alternatively, there may be ways to increase the sensitivity of cells to temperatures that can be achieved currently, such as pH reduction or chemosensitization.