Bruce N. Gray

Magnetically mediated hyperthermia: current status and future directions

The use of hyperthermia in the treatment of cancers is appealing because, as a physical therapy, hyperthermia would have far fewer restrictive side effects than chemotherapy and radiotherapy, and it could be used in combination with these therapies. However, the currently available modalities of hyperthermia are often limited by their inability to selectively target tumour tissue and, hence, they carry a high risk of collateral organ damage or they deposit heat in a very localized manner which can result in under-treatment of a tumour. Magnetically mediated hyperthermia (MMH) has the potential to address these shortcomings. MMH consists of the localization of magnetic particles or seeds within tumour tissue followed by exposure to an externally applied alternating magnetic field to cause them to heat. Since this concept was introduced (over 40 years ago), MMH has evolved into four general sub-classes: arterial embolization hyperthermia (AEH), direct injection hyperthermia (DIH), intracellular hyperthermia (IH) and interstitial implant hyperthermia (IIH). It is the purpose of this article to review these four sub-classes in terms of experimental or clinical results, advantages, limitations and current status.

Selective internal radiation therapy: Distribution of radiation in the liver

Selective internal radiation therapy for primary and secondary liver cancer involves the intra-hepatic arterial injection of microspheres containing yttrium-90. The microspheres become entrapped primarily in, and thus preferentially irradiate, tumour tissue. During a clinical trial with this therapy it has been possible to take tumour and normal liver tissue samples, after microsphere injection, and measure their specific activity. Absorbed tissue radiation doses were then calculated for tumour and normal tissue samples from a total of nine patients. The mean tumour to normal tissue ratio for radiation dose for the nine patients was approximately 6:1 with a range of 0.4:1-45:1. Injection of similar amounts of activity in different patients resulted in markedly differing tissue doses depending on liver size and tumour burden. Normal liver tissue doses of between 9 and 75 Gy were measured while corresponding tumour tissue doses ranged from 34 to 147 Gy. Selective internal radiation therapy, combined with the blood flow changes resulting from angiotensin II administration, can provide preferentially high radiation doses to tumour tissue within the liver whilst relatively sparing the surrounding normal liver tissue.

Distribution of different sized microspheres in experimental hepatic tumours

The extent of embolization of different sized radioactive microspheres in experimental tumours and the homogeneity of their distribution in normal liver was examined in 25 rats. The ratio of arterially introduced microspheres lodging in tumour tissue compared to the surrounding normal hepatic parenchyma was measured for 15, 32.5 and 50 microns diameter tracer microspheres. The mean tumour to liver arterial perfusion ratio (T/L) for 15 and 32.5 microns spheres was approximately 3:1 in both cases and there was no significant difference between these values (P greater than 0.05). However, 50 microns microspheres did not preferentially lodge in malignant tissue (mean T/L ratio 1:1). The homogeneity of distribution of microspheres embolizing in the normal liver tissue was assessed for each microsphere size. As microsphere diameter increased from 15 to 50 microns, microspheres lodged more evenly throughout the liver substance. For 15 microns microspheres the coefficient of variation was 55.5% +/- 8.3 and 32.5 microns microspheres distributed with a coefficient of 35% +/- 16.8 while 50 microns spheres distributed most evenly with a coefficient of 19.7% +/- 6.8.

Treatment of experimental rabbit liver tumours by selectively targeted hyperthermia

Experimental rabbit liver tumours were preferentially heated to therapeutic temperatures without compromising the surrounding normal hepatic parenchyma. This was achieved by the use of hepatic arterially infused ferromagnetic microspheres that heat as a result of magnetic hysteresis loss when exposed to an alternating magnetic field. Treatment sessions involving a single 20-min exposure to the alternating field resulted in total suppression of tumour growth at 14 days compared to controls, in which tumour sizes increased dramatically over the same period. Histopathological examination of treated tumour sections showed total tumour destruction in some cases. Separate animal groups used to control for the effects of the embolized microspheres alone and for the effect of the applied magnetic field yielded similar tumour growth responses to a control group with no intervention whatsoever. The achievement of positive temperature differentials between tumour and normal liver and the consequent therapeutic responses encourages further development of this technology for the treatment of liver cancer in humans.

Evaluation of ion-exchange microspheres as carriers for the anticancer drug doxorubicin : in-vitro studies

Abstract— A comparison study of doxorubicin loading, release characteristics and stability within sodium and hydrogen forms of ion‐exchange resin microspheres has been performed. It was demonstrated that resins in the Na+ form, although having lower drug loading capacity, showed similar release profiles to resins in the H+ form but still maintain all the drug activity. Resins in the H+ form, despite having high drug loading capacity, caused drug degradation within microspheres due to their strong acidic nature. Therefore, in comparison with the H+ form, resins in the Na+ form can be considered as better carriers for doxorubicin in terms of sustaining the release of drug and maintaining drug activity. Other factors such as the degree of resin cross‐linkage and drug/resin mixing time have also been examined in relation to drug loading and release characteristics. Overall, this study demonstrated the significance of the characteristics of matrix materials and their influence on the drug activity and microsphere performance in‐vitro.

Effect of angiotensin II on blood flow in the transplanted sheep squamous cell carcinoma

The effects of systemic infusion of angiotensin II on the distribution of blood flow in the sheep squamous cell carcinoma after transplantation to the liver were measured using tracer microspheres. The ratio of arterially introduced radioactive microspheres embolizing in tumour tissue compared to normal hepatic parenchyma was measured before and after infusion of angiotensin II. Doses of angiotensin II inducing increases in mean arterial blood pressure of 26 mmHg produced significant increases in the embolization ratio from 2.8 to 4.1:1. In addition, the ratio of microspheres gaining access to the necrotic centres of the tumours compared to the normal liver tissue significantly increased from 1.6 to 2.3:1. In terms of the technique of internal radiation therapy for hepatic metastases, the concurrent infusion of angiotensin II with injection of radioactive microspheres would result in a substantially enhanced radiation dose to liver tumours. At the same time the dose to normal tissue can be minimized.

The effect of tumour size on ferromagnetic embolization hyperthermia in a rabbit liver tumour model.

Objective : Ferromagnetic Embolization Hyperthermia (FEH) consists of arterially embolizing tumours with ferromagnetic particles to cause hysteretic heating upon subsequent exposure to an alternating magnetic field. The objective was to determine the effect of tumour size during FEH using a rabbit liver tumour model. Method : Thirty-three rabbits containing implanted hepatic VX2 carcinomas received a hepatic arterial infusion of ferromagnetic particles suspended in lipiodol. Following hysteretic heating, tumour and normal hepatic tissues were chemically analysed for iron content. Tumours were classed as small if their mass was less than the median mass for the whole group of subjects (2.1g), and as large if their mass was greater than or equal to the median. To control for variability in tumour iron concentration, 13 small tumours were matched to 13 large tumours by iron concentration, and their heating characteristics compared. Results : The heating rate in large tumours (median = 5.0°C/min) was significantly greater than that in the matched small tumours (median = 2.8°C/min), p = 0.006. Regression analysis determined that the slope of the heating rate vs iron concentration curve for large tumours was 1.5 times greater than that for the matched small tumours, p < 0.001. After cessation of heating in large tumours, there was continued heat dissipation into surrounding tissues, which led to anomalous temperature increases. There was an inverse linear relationship between tumour size and tumour iron concentration for a given dose of particles. Conclusion : For a given tumour iron concentration, larger tumours heat at a greater rate than small tumours, due to the poorer tissue cooling and better heat conduction in the necrotic regions of large tumours. This warrants further investigation as this finding could confer a significant advantage on FEH over other hyperthermic modalities in the treatment of hepatic malignancies.

Resecting large numbers of hepatic colorectal metastases

Background: Despite the widespread use of surgical resection as a treatment for hepatic colorectal metastases, the value of resecting more than three metastases remains controversial. It was the objective of this study to determine if resection of larger numbers of metastases affects patient survival.

Internal radiotherapy for hepatic metastases II: The blood supply to hepatic metastases

Given that metastatic hepatic malignancy remains as a significant cause of death, with a median survival after diagnosis of only 7 months despite treatment, there exists a need for some effective treatment modality. Internal radiotherapy in the form of yttrium-90 microspheres infused into the hepatic artery appears to be a promising method of therapy. One criterion required for the success of this treatment is that of a differentially greater arterial supply to tumor as opposed to liver tissue. This arterial hypervascularity of tumor has been demonstrated before. However, some conflict has been reported as to the maintenance of this state as tumor size increases. Using 15 micrometers Cobalt-57 microspheres for studying salivary adenocarcinoma implants in DA rat livers, these experiments have demonstrated a constant blood flow in the tumor periphery of 3.9 times that within the normal hepatic parenchyma, regardless of tumor size. Also demonstrated is a progressive decrease in central tumor arterial blood flow after a tumor diameter of 6 mm has been exceeded. Arterial hypervascularity of liver tissue adjacent to the tumor has been demonstrated while an intermediate zone of liver tissue appeared hypovascular, suggesting the presence of shunting. In three humans with metastatic liver disease, hepatic artery infusion of particulate radiotracer has demonstrated the peripheral tumor hypervascularity and relative central tumor hypovascularity with good correlation obtained with the images of the metastases on conventional colloidal hepatic scintigraphy. This method allows assessment of the patients suitability for internal radiotherapy by enabling assessment of the tumor vascularity and the degree of potentially dangerous extrahepatic irradiation.

Internal radiotherapy for hepatic metastases I: The homogeneity of hepatic arterial blood flow

Internal radiotherapy, in the form of arterially infused yttrium-90-labeled microspheres, theoretically appears encouraging as a method of treatment for hepatic metastases. Previous investigators have assumed a homogeneous distribution of these microspheres and given dosages of isotope based solely on an estimated liver mass. The purpose of this study has been to establish the homogeneity of isotope distribution in liver substance when 15 micrometers microspheres are arterially injected. This has been done in three mammalian species, with the results expressed as a mean percentage coefficient of variation of 28 +/- 5%. Also demonstrated is the fact that 15 micrometers particles, while not penetrating to the venous circulation, achieve a more homogeneous spread throughout the liver than larger particles. It has been demonstrated that to achieve this maximum homogeneity distribution, 4000 beads/g of liver tissue are required. This equates in the therapeutic situation to a maximum activity of 4 Ci/g of infused microspheres. These results are considered significant in that they indicate criteria necessary to achieve the maximum homogeneity of therapeutic agent within liver substance when it is administered by this method, and will allow confidence limits to be attached to direct in vivo measurement of hepatic irradiation.