S. B. Field

Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: Results from five randomized controlled trials

PURPOSE Claims for the value of hyperthermia as an adjunct to radiotherapy in the treatment of cancer have mostly been based on small Phase I or II trials. To test the benefit of this form of treatment, randomized Phase III trials were needed. METHODS AND MATERIALS Five randomized trials addressing this question were started between 1988 and 1991. In these trials, patients were eligible if they had advanced primary or recurrent breast cancer, and local radiotherapy was indicated in preference to surgery. In addition, heating of the lesions and treatment with a prescribed (re)irradiation schedule had to be feasible and informed consent was obtained. The primary endpoint of all trials was local complete response. Slow recruitment led to a decision to collaborate and combine the trial results in one analysis, and report them simultaneously in one publication. Interim analyses were carried out and the trials were closed to recruitment when a previously agreed statistically significant difference in complete response rate was observed in the two larger trials. RESULTS We report on pretreatment characteristics, the treatments received, the local response observed, duration of response, time to local failure, distant progression and survival, and treatment toxicity of the 306 patients randomized. The overall CR rate for RT alone was 41% and for the combined treatment arm was 59%, giving, after stratification by trial, an odds ratio of 2.3. Not all trials demonstrated an advantage for the combined treatment, although the 95% confidence intervals of the different trials all contain the pooled odds ratio. The greatest effect was observed in patients with recurrent lesions in previously irradiated areas, where further irradiation was limited to low doses. CONCLUSION The combined result of the five trials has demonstrated the efficacy of hyperthermia as an adjunct to radiotherapy for treatment of recurrent breast cancer. The implication of these encouraging results is that hyperthermia appears to have an important role in the clinical management of this disease, and there should be no doubt that further studies of the use of hyperthermia are warranted.

Induced thermal resistance in the mouse ear

The mouse ear (pinna) was used to investigate the effect of two hyperthermic treatments. Heating was by immersion in hot water at 43.5 degrees C. A single treatment of about 50 minutes was required to cause necrosis in 50% of the ears heated. When heat treatment was given in two equal fractions the total heating time had to be increased if the interval between fractions was greater than four hours. By 24 hours a total treatment of about 100 minutes was required, indicating almost complete recovery from the first heating. Priming treatments at 43.5 degrees C induced thermal resistance to a second heat treatment at 43.5 degrees C. Maximum resistance was observed one day after a 20 minute priming and two days after a 40 minute priming, when the heating time had to be increased to 120 minutes, an increase by a factor of 2.4. Shorter priming treatments induced less resistance, the minimum heating time to produce an effect being two minutes. In all cases the effect decreased during the next four to five days. These results indicate that the reduced response of tissues to fractionated hyperthermia is due both to the repair of sublethal heat damage and induction of thermal resistance.

The response of the mouse ear to heat applied alone or combined with X rays

Abstract The effects of heat either alone or combined with Xirradiation were investigated in the skin of the mouse ear. Ears were heated for times ranging from 7.5 minutes to four hours in a water-bath at temperatures ranging from 39°C to 46 °C. Severe heat treatment caused necrosis during the first few days after heating. Mild hyperthermia, which itself caused early transient reddening but no further visible changes, when given immediately after X rays enhanced the radiodermatitis which was observed during 10–50 days after treatment. From a level of heating which is slightly less than that required to produce necrosis in any mice, an increase in temperature of 0.5°C caused an increase in the incidence of necrosis from 0 to 100%. For hyperthermia which enhanced radiodermatitis, an increase of 0.5°C was equivalent to an increase in X-ray dose of 10 to 15%. For heat alone, the time required to produce necrosis in half the treated mice was reduced by one half for a rise in temperature of 1 °C. For heat combi...

An assessment of local hyperthermia in clinical practice

A total of 116 small superficial tumours have been treated by radiation alone, hyperthermia alone, or radiation and hyperthermia combined in a Phase I/II study. Most tumours were metastases or local recurrences of adenocarcinoma of breast but other histologies were involved including melanoma. Hyperthermia was delivered predominantly by microwaves, but radiofrequency and ultrasound methods were also used. Rigorous thermal dosimetry, based on measurements from invasive multipoint thermocouple arrays, has shown that 58 per cent of hyperthermal treatments reached a minimum dose within tumour equivalent to 20 min at 43 degrees C (minEq43); 24 per cent reached at least 60 minEq43. Minima of 20 minEq43 were achieved successfully on every intended occasion in a quarter of the 75 tumours heated, and on one/two occasions in 39; unfortunately, this minimum threshold was not reached at any point monitored at any hyperthermia session in 17(23 per cent) tumours. Tumours that received radiation and effective hyperthermia were more likely to disappear completely (CR rate 86 per cent) than those that were irradiated but inadequately heated (CR rate 35 per cent) (P less than 0.001) or were treated by the same doses of radiation alone (CR rate 35 per cent) (P less than 0.05). This improvement with hyperthermia became more apparent with suboptimal radiation doses. A small but measurable growth delay was imposed by heat alone with a poor complete response rate (11 per cent). The real-time use of a thermal dose unit in clinical practice facilitates hyperthermal treatment comparisons and provides an important parameter for checking the technical performance of a heat delivery system. The results of this study emphasizes the need for improvements in intratumour temperature distribution, in order to establish minimum threshold temperatures to enhance tumour response rates.

The effect of local hyperthermia on the small intestine of the mouse

Small loops of mouse jejunum were exteriorized and heated by immersion in a bath of Krebs-Ringer salt solution. Crypts were lost in the heated regions with a half-time of approximately six hours and reached a steady level of damage by 10--16 hours. There was no recovery in crypt number for one week after hyperthermia. Using a 24 hour assay, crypt survival curves were obtained using various heating times in the temperature range 37.5 degrees C--44.5 degrees C. These curves were qualitatively similar to those resulting from radiation damage, showing a shoulder followed by exponential killing. As the temperature was increased, progressive changes in shape of the curves indicated a proportional inhibition of accumulation of sublethal heat damage combined with increased rate of expression of lethal damage. Over the temperature range 42.3 degrees C--44.5 degrees C, a linear relationship was found between the rate of crypt loss and the reciprocal of the absolute temperature. An activation energy of 600 +/- 70 kJ mole-1 was calculated using the Arrhenius equation. In this temperature range, doubling the heating time had the same effect as increasing the temperature by 1 degree C. At temperatures below about 42.3 degrees C, the tissue became relatively less sensitive to increasing the treatment time.

The response of the rat tail to hyperthermia

When the cartilage of the tail of a baby rat is exposed to temperatures between 41 degrees C and 46 degrees C either necrosis or a small degree of stunting in growth may occur. Isoeffect curves relating time and temperature for both these endpoints for normal and clamped tissue were found to be parallel, a doubling of heating time or an increase in temperature of 1 degree C having the same effect in all cases. Clamping sensitizes the tails by a factor of about three in heating time, equivalent to a temperature difference of 1.5 degrees C. Arrhenius plots show an inactivation energy of 140 kcal/mole. This is similar to that found by other workers using different endpoints, and supports the suggestion that protein denaturation is a critical target for direct heat damage.

Collagen Content of Lungs of Mice after X-Ray Irradiation

To investigate the development of late radiation fibrosis in lungs large single doses of X rays were given to the hemithoraxes of mice. Hydroxyproline, an amino acid specific to collagen, was estimated in both irradiated and shielded lungs up to 48 weeks after exposure. There was a dose dependent atrophy of the irradiated lung and a compensatory hypertrophy of the shielded lung. The hydroxyproline per gram of dry irradiated lung increased between 24 and 36 weeks after 2000-4000 rad with no further change up to 48 weeks. Both total hydroxyproline content and dry weight of irradiated lungs decreased but after 24 weeks the histological appearance was that of collagen deposition after edema and hyperplasia. It is concluded that collagen deposition occurs at a late stage in the reorganization after radiation injury to mouse lung and is therefore probably not the cause of 80-180 day death after exposure of the whole thorax.

The response of tissues to combined hyperthermia and X rays

Three normal tissues in mice and rats (skin, intestine and cartilage) have been used to investigate the effects of combined hyperthermia and radiation. The heating time was kept constant at one hour and X rays were given either immediately before or after heating. Thermal enhancement ratios were measured as a function of temperature up to 43 degress C and were compared with data for other normal tissues and tumours taken from the literature. The variation from tissue to tissue was found to be fairly small within this temperature range, but there is some indication of a greater response of tumours.

Damage to Mouse Lung with Fractionated Neutrons and X Rays

The relative biological effectiveness (RBE) for damage to mouse lung was measured for single doses and up to 30 fractions of 8 MV x rays and fast neutrons, relative to 250 kVp x rays. With 8 MV x rays the RBE was 0.87 and did not vary with dose per fraction between 150 and 1200 rad. With fast neutrons the RBE did not vary from 1.5 at 1200 rad of x rays, which is about 30% lower than that for skin, to 3.7 at 150 rad of x rays, which is about 10% less than that for skin. The implications for treatment of the lung with fast neutrons are discussed.

The Relationship between Early and Late Radiation Damage in Rodents' Skin

A study is made of the relationship between early and late damage after irradiation of the feet or ears of rats. In one type of experiment in which large groups of animals were given the same dose, there was a good correlation between the early and late forms of damage. In another experiment, the relationship between these two forms of radiation damage was found to be unaltered by a single dose of X-rays given 8 months earlier. Thus, both types of experiment point to the early and late forms of reaction in the skin of rodents resulting from a common cause. Other relevant experimental data and their relationship to clinical observations are discussed.