Quality assurance guidelines for interstitial hyperthermia.

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

The Kadota Fund International Forum 2004--clinical group consensus.

The results from experimental studies indicate that hyperthermia is both an effective complementary treatment to, and a strong sensitiser of, radiotherapy and many cytotoxic drugs. Since the first international hyperthermia conference in 1975, Washington DC, techniques to increase tumour temperature have been developed and tested clinically. Hyperthermia can be applied by several methods: local hyperthermia by external or internal energy sources, perfusion hyperthermia of organs, limbs, or body cavities, and whole body hyperthermia. The clinical value of hyperthermia in combination with other treatment modalities has been shown by randomised trials. Significant improvement in clinical outcome has been demonstrated for tumours of the head and neck, breast, brain, bladder, cervix, rectum, lung, oesophagus, for melanoma and sarcoma. The addition of hyperthermia resulted in remarkably higher (complete) response rates, accompanied by improved local tumour control rates, better palliative effects, and/or better overall survival rates. Toxicity from hyperthermia cannot always be avoided, but is usually of limited clinical relevance. In spite of these good clinical results, hyperthermia has received little attention. Problems with acceptance concern the limited availability of equipment, the lack of awareness concerning clinical results, and the lack of financial resources. In this paper the most relevant literature describing the clinical effects of hyperthermia is reviewed and discussed, and means to overcome the lack of awareness and use of this modality is described.

ROS production and angiogenic regulation by macrophages in response to heat therapy.

PURPOSE: It has been well established that inadequate blood supply combined with high metabolic rates of oxygen consumption results in areas of low oxygen tension (<1%) within malignant tumours and that elevating tumour temperatures above 39 degrees Celsius results in significant improvement in tumour oxygenation. Macrophages play a dual role in tumour initiation and progression having both pro-tumour and anti-tumour effects. However, the response of macrophages to heat within a hypoxic environment has not yet been clearly defined. METHODS: Raw 264.7 murine macrophages were incubated under normoxia and chronic hypoxia at temperatures ranging from 37-43 degrees Celsius. Under normoxia at 41 degrees Celsius, macrophages start to release significant levels of superoxide. The combination of heat with hypoxia constitutes an additional stimulus leading to increased respiratory burst of macrophages. RESULTS: The high levels of superoxide were found to be associated with changes in macrophage production of pro-angiogenic cytokines. While hypoxia alone (37 degrees Celsius) increased levels of hypoxia inducible factor-1alpha (HIF-1alpha) in macrophages, the combination of hypoxia and mild hyperthermia (39-41 degrees Celsius) induced a strong reduction in HIF-1alpha expression. The HIF-regulated vascular endothelial growth factor (VEGF) decreased simultaneously, revealing that heat inhibits both HIF-1alpha stabilization and transcriptional activity. CONCLUSION: The data suggest that temperatures which are readily achievable in the clinic (39-41 degrees Celsius) might be optimal for maximizing hyperthermic response. At higher temperatures, these effects are reversed, thereby limiting the therapeutic benefits of more severe hyperthermic exposure.

Effect of calcitonin gene related peptide vs sodium nitroprusside to increase temperature in spontaneous canine tumours during local hyperthermia.

The objectives of this study were to compare the effects of two vasodilators, sodium nitroprusside (SNP) and calcitonin gene-related peptide (CGRP) on mean arterial pressure (MAP), heart rate (HR) and temperatures in tumour and surrounding normal tissue during local hyperthermia treatment. Eleven tumour-bearing pet dogs with spontaneous soft tissue sarcomas were given SNP intravenously during local hyperthermia. The drug infusion rate was adjusted to maintain a 20% decrease in MAP. The median (95% CI) increase in the temperature distribution descriptors T(90) and T(50) was 0.2 degrees C (0.0-0.4 degrees C, p = 0.02) and 0.4 degrees C (0.1-0.7 degrees C, p = 0.02), respectively, in tumour. Normal subcutaneous tissue temperatures were mildly increased but remained below the threshold for thermal injury. The effects of CGRP were investigated in six tumour-bearing dogs following a protocol similar to that used for SNP. The median (interquartile (IQ) range) decrease in mean arterial pressure was 19% (15-26%) after CGRP administration and a significant increase was seen in tumour but not normal subcutaneous tissue temperatures. The median (95% CI) increase in the temperature distribution descriptors T(90) and T(50) was 0.5 degrees C (0.1-1.6 degrees C, p = 0.03) and 0.8 degrees C (0.1-1.6 degrees C, p = 0.13), respectively. Administration of SNP or CGRP did not result in local or systemic toxicity in tumour-bearing dogs. However, the magnitude of increase in tumour temperatures was not sufficient to improve the likelihood of increased response rates. Therefore, there is little justification for translation of this approach to human trials using conventional local hyperthermia.

Physiological mechanisms underlying heat-induced radiosensitization.

The objective of this review is to evaluate hyperthermia related changes in tumor physiologic parameters and their relevance for tumor radiosensitization with particular emphases on tumor oxygenation. Elevation of temperature above the physiological level causes changes in blood flow, vascular permeability, metabolism, and tumor oxygenation. These changes in addition to the cellular effects such as direct cytotoxicity, inhibition of potentially lethal damage and sublethal damage repair, have an important influence on the efficacy of radiotherapy. There is now clear evidence that in a variety of rodent and canine, as well as human tumors, the changes in tumor oxygenation status caused by hyperthermia are temperature dependent and this relationship may greatly influence the response of tumors to thermoradiotherapy. The improvement of tumor oxygenation after mild hyperthermia, which often lasts for as long as 24-48 h after heating, may increase the likelihood of a positive response of tumors to radiation therapy. Furthermore, the activity of some chemotherapy drugs is also oxygen dependent, therefore, the heat-induced increase in tumor oxygenation may significantly increase the effectiveness of thermoradiotherapy in combination with certain chemotherapy drugs. Further investigations remain to be conducted to obtain clearer insights into the relationship between thermal parameters, oxygenation and response of human tumors to hyperthermia in combination with radiotherapy and/or chemotherapy.

Ultrasound guided pO2 measurement of breast cancer reoxygenation after neoadjuvant chemotherapy and hyperthermia treatment.

The objective of this study was to determine whether neoadjuvant chemotherapy in combination with hyperthermia (HT) would improve oxygenation in locally advanced breast tumours. The study describes a new optimized ultrasound guided technique of pO2 measurement using Eppendorf polarographic oxygen probes in 18 stage IIB-III breast cancer patients. Prior to treatment, tumour hypoxia (median pO2<10 mmHg) was present in 11/18 patients (average median pO2=3.2 mmHg). Seven patients had well oxygenated tumours (median pO2 of 48.3 mmHg). Eight patients with hypoxic tumours prior to treatment had a significant improvement (p=0.0008) in tumour pO2 after treatment (pO2 increased to 19.2 mmHg). In three patients, tumours remained hypoxic (average median pO2=4.5 mmHg). The advantages of the ultrasound guided pO2 probe are in the accuracy of the Eppendorf electrode placement in tumour tissue, the ability to monitor electrode movement through the tumour tissue during the measurement and the ability to avoid electrode placement near or in large blood vessels by using colour Doppler imaging. The results of this preliminary study suggest that the combination of neoadjuvant chemotherapy and hyperthermia improves oxygenation in locally advanced breast tumours that are initially hypoxic.

Temperature-dependent changes in physiologic parameters of spontaneous canine soft tissue sarcomas after combined radiotherapy and hyperthermia treatment.

PURPOSE: The objectives of this study were to evaluate effects of hyperthermia on tumor oxygenation, extracellular pH (pHe), and blood flow in 13 dogs with spontaneous soft tissue sarcomas prior to and after local hyperthermia. METHODS AND MATERIALS: Tumor pO2 was measured using an Eppendorf polarographic device, pHe using interstitial electrodes, and blood flow using contrast-enhanced magnetic resonance imaging (MRI). RESULTS: There was an overall improvement in tumor oxygenation observed as an increase in median pO2 and decrease in hypoxic fraction (% of pO2 measurements <5 mm Hg) at 24-h post hyperthermia. These changes were most pronounced when the median temperature (T50) during hyperthermia treatment was less than 44 degrees C. Tumors with T50 > 44 degrees C were characterized by a decrease in median PO2 and an increase in hypoxic fraction. Similar thermal dose-related changes were observed in tumor perfusion. Perfusion was significantly higher after hyperthermia. Increases in perfusion were most evident in tumors with T50 < 44 degrees C. With T50 > 44 degrees C, there was no change in perfusion after hyperthermia. On average, pHe values declined in all animals after hyperthermia, with the greatest reduction seen for larger T50 values. CONCLUSION: This study suggests that hyperthermia has biphasic effects on tumor physiologic parameters. Lower temperatures tend to favor improved perfusion and oxygenation, whereas higher temperatures are more likely to cause vascular damage, thus leading to greater hypoxia. While it has long been recognized that such effects occur in rodent tumors, this is the first report to tie such changes to temperatures achieved during hyperthermia in the clinical setting. Furthermore, it suggests that the thermal threshold for vascular damage is higher in spontaneous tumors than in more rapidly growing rodent tumors.

Acute pancreatitis associated with administration of a nitric oxide synthase inhibitor in tumor-bearing dogs.

BACKGROUND: Nitric oxide synthase (NOS) inhibitors have been investigated as potential cytotoxic agents to treat tumors lacking p53 function. Furthermore, their ability to reduce tumor blood flow can be combined with drugs that are specifically designed to kill cells that are hypoxic or to improve temperatures during local heat (hyperthermia) treatment of tumors. This paper reports the unexpected development of acute pancreatitis in two tumor-bearing pet dogs that were treated with the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) during administration of local hyperthermia. METHODS: Prior to the use of L-NAME in tumor-bearing dogs, purpose-bred beagles were studied. Following induction of inhalation anesthesia, local hyperthermia was applied to either normal thigh muscle (beagles) or tumors (tumor-bearing dogs). Once a thermal steady state was achieved, L-NAME was administered and temperature monitoring continued. Animals were observed after treatment for evidence of toxicity. RESULTS: The beagles tolerated the treatment well, with no side effects noted either clinically or by routine CBC or blood chemistry analyses. In contrast, the first two tumor-bearing dogs accrued onto the phase I study developed acute pancreatitis in the immediate post-treatment period which necessitated hospitalization and intensive care. The trial was stopped. Both dogs had intercurrent risk factors which predisposed them to development of pancreatitis, although neither had a history of symptoms of pancreatitis at the time the hyperthermia + L-NAME treatment was given. CONCLUSIONS: We conclude that caution should be exercised when considering NOS inhibition for cancer treatment. Careful evaluation of history and health status as well as recognition of potential risk factors may be key in avoiding potentially fatal complications. This study demonstrates the value of performing potentially harmful treatments in tumor-bearing dogs prior to introduction into the human clinic.

Effects of intraoperative irradiation (IORT) and intraoperative hyperthermia (IOHT) on canine sciatic nerve: histopathological and morphometric studies.

PURPOSE/OBJECTIVE: Peripheral neuropathies have emerged as the major dose-limiting complication reported after intraoperative radiation therapy (IORT). The combination of IORT with hyperthermia may further increase the risk of peripheral nerve injury. The objective of this study was to evaluate histopathological and histomorphometric changes in the sciatic nerve of dogs, after IORT with or without hyperthermia treatment. METHODS AND MATERIALS: Young adult beagle dogs were randomized into five groups of 3-5 dogs each to receive IORT doses of 16, 20, 24, 28, or 32 Gy. Six groups of 4-5 dogs each received IORT doses of 12, 16, 20, 24, or 28 Gy simultaneously with 44 degrees C of intraoperative hyperthermia (IOHT) for 60 min. One group of dogs acted as hyperthermia-alone controls. Two years after the treatment, dogs were euthanized, and histopathological and morphometric analyses were performed. RESULTS: Qualitative histological analysis showed prominent changes such as focal necrosis, mineralization, fibrosis, and severe fiber loss in dogs which received combined treatment. Histomorphometric results showed a significantly higher decrease in axon and myelin and small blood vessels, with a corresponding increase in connective tissue in dogs receiving IORT plus hyperthermia treatment. The effective dose for 50% of nerve fiber loss (ED50) in dogs exposed to IORT only was 25.3 Gy. The ED50 for nerve fiber loss in dogs exposed to IORT combined with IOHT was 14.8 Gy. The thermal enhancement ratio (TER) was 1.7. CONCLUSION: The probability of developing peripheral neuropathies in a large animal model is higher when IORT is combined with IOHT, when compared to IORT application alone. To minimize the risk of peripheral neuropathy, clinical treatment protocols for the combination of IORT and hyperthermia should not assume a thermal enhancement ratio (TER) to be lower than 1.5.

Effects of intraoperative irradiation and intraoperative hyperthermia on canine sciatic nerve: neurologic and electrophysiologic study.

PURPOSE: Late radiation injury to peripheral nerve may be the limiting factor in the clinical application of intraoperative radiation therapy (IORT). The combination of IORT with intraoperative hyperthermia (IOHT) raises specific concerns regarding the effects on certain normal tissues such as peripheral nerve, which might be included in the treatment field. The objective of this study was to compare the effect of IORT alone to the effect of IORT combined with IOHT on peripheral nerve in normal beagle dogs. METHODS AND MATERIALS: Young adult beagle dogs were randomized into five groups of three to five dogs each to receive IORT doses of 16, 20, 24, 28, or 32 Gy to 5 cm of surgically exposed right sciatic nerve using 6 MeV electrons and six groups of four to five dogs each received IORT doses of 0, 12,16, 20, 24, or 28 Gy simultaneously with 44 degrees C of IOHT for 60 min. IOHT was performed using a water circulating hyperthermia device with a multichannel thermometry system on the surgically exposed sciatic nerve. Neurologic and electrophysiologic examinations were done before and monthly after treatment for 24 months. Electrophysiologic studies included electromyographic (EMG) examinations of motor function, as well as motor nerve conduction velocities studies. RESULTS: Two years after treatment, the effective dose for 50% complication (ED50) for limb paresis in dogs exposed to IORT only was 22 Gy. The ED50 for paresis in dogs exposed to IORT combined with IOHT was 15 Gy. The thermal enhancement ratio (TER) was 1.5. Electrophysiologic studies showed more prominent changes such as EMG abnormalities, decrease in conduction velocity and amplitude of the action potential, and complete conduction block in dogs that received the combination of IORT and IOHT. The latency to development of peripheral neuropathies was shorter for dogs exposed to the combined treatment. CONCLUSION: The probability of developing peripheral neuropathies in a large animal model was higher for IORT combined with IOHT, than for IORT alone. The dose required to produce the same level of late radiation injury to the sciatic nerve was reduced by a factor of 1.5 (TER) if IORT was combined with 44 degrees C of IOHT for 60 min.

Combining radiation therapy with other treatment modalities.

Combining treatment modalities is indicated when single modality treatment does not result in adequate tumor control, or if the cosmetic or functional outcome of single modality treatment is less than desirable. The combination of surgery and radiation has proven useful in the treatment of both human and veterinary patients. Surgery can be used to remove large, bulky tumors whereas radiation therapy eliminates the subclinical disease adjacent to the tumor mass that invades important normal tissue structures. If properly combined, the result should be better tumor control combined with a better functional and cosmetic outcome. Radiation therapy can be administered preoperatively, postoperatively, and intraoperatively, depending on a variety of factors. Radiation therapy combined with hyperthermia has a strong scientific rationale. Hyperthermia is particularly effective against some cells, such as those in late S-phase, that are resistant to radiation therapy. Nutrient-deprived cells and cells with low pH are also very sensitive to hyperthermia, and these may reflect areas in a tumor where hypoxia may be present. Therapeutic gain has been shown in randomized clinical trials combining radiation therapy and hyperthermia in tumor bearing dogs. However, the disadvantage of hyperthermia for both human and veterinary tumors remains the inability to adequately maintain uniform temperatures to the tumors. Chemotherapy is an important adjuvant to radiation therapy for the control of distant tumor spread. The scientific rationale for combining chemotherapy with radiation therapy for local control is less clear, and is complex because of a variety of factors.

Effects of intraoperative hyperthermia on canine sciatic nerve: histopathologic and morphometric studies.

Failure to achieve local control in the treatment of pelvic and retroperitoneal tumours results in a high rate of recurrences. The objective of intraoperative hyperthermia (IOHT) is to enhance the effect of intraoperative radiation therapy and to increase local tumour control. The tolerance of peripheral nerves to heat may limit the heat dose that can be applied to tumours. Histopathologic and histomorphometric changes of canine sciatic nerve after 60-min IOHT were studied in three groups of five dogs each for temperatures of 43, 44 and 45 degrees C. IOHT was performed using a water-circulating hyperthermia device with a multichannel thermometry system on surgically exposed sciatic nerve. Histopathologic and histomorphometric studies were done immediately, 3 weeks and 12 months after IOHT. Histologic changes observed immediately after treatment were minimal but at 3 weeks following 60-min 45 degrees C IOHT both axon and myelin loss and an increase in endoneurial fibrous tissue were observed. Twelve months after treatment a statistically significant decrease in axon, myelin and small vessel percentages as well as an increase in endoneurial and epineural connective tissue were observed for dog treated to 45 degrees C. Dog treated to 44 degrees C for 60 min had similar statistically significant but less severe changes. Twelve months after 43 degrees C IOHT for 60 min, nerve fibres appeared normal and endoneurial connective tissue was only increased mildly around small and medium-sized vessels. These results suggest that temperatures to the peripheral nerve > 44 degrees C for 60 min are likely to cause significant histopathologic changes that can be found 12 months after treatment. A hypothesis of the mechanism of heat injury to peripheral nerves was developed.

Effects of intraoperative hyperthermia on peripheral nerves: neurological and electrophysiological studies.

The tolerance of peripheral nerves to heat may limit the heat dose which can be applied to tumours. This may be particularly important in intraoperative hyperthermia (IOHT) for pelvic and retroperitoneal tumours. Furthermore the effects of hyperthermia alone must be known before its effects can be assessed in combination with irradiation. In this study injury to sciatic nerves was evaluated in 30 beagle dogs for 1 year following IOHT. IOHT was performed using a water circulating hyperthermia device with multichannel thermometry system. Neurological and electrophysiological examinations were done before, during and after IOHT treatment. Electrophysiological examinations showed a significant decrease in sciatic nerve conduction velocity and potential amplitude immediately after 60 min of heating for all temperatures. The greatest decrease in conduction velocity was observed for a temperature of 45 degrees C. Full recovery of nerve conduction velocity was observed 3 weeks following hyperthermia for all dogs except for those exposed to 45 degrees C. Neurological findings correlated with electrophysiological results. All five dogs which had nerve exposed to 45 degrees C for 60 min had severe neurological changes, with recovery taking place between 3 and 11 months after treatment. Based on these results it appears that temperatures to the peripheral nerve exceeding 44 degrees C for 1 h are likely to cause significant, but not necessarily permanent, nerve injury.