Radiotherapy with curative intent was administered to 159 of 167 consecutively admitted patients with nasopharyngeal carcinoma. The classification (UICC 1982) gave the staging: stage I 8%, stage II 2%, stage III 28%, and stage IV 61%. The actuarial local tumor control was 54% and correlated to the T-classification. Primary control of neck nodes was 67% but was not correlated to the N-classes. Distant failure occurred in 20% of the patients; this was correlated to the N-classification. The 10-year actuarially corrected survival rate was 37% (stage I+II 60%, stage III 49%, stage IV 27%). Late reactions were seen in 69%, and most patients had mild to moderate xerostomia. Men with high hemoglobin had a better prognosis than men with values in the lower part of the normal range. It is concluded that primary control in the T- and N-positions is the parameter most crucial to success.

Actuarial Analysis↗

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Potentiation of the anti-tumour effect of hyperthermia by combining with the vascular targeting agent 5,6-dimethylxanthenone-4-acetic acid.

The potential of the vascular targeting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) to enhance the effect of hyperthermia was investigated in a C3H mouse mammary carcinoma grown in the feet of female CDF1 mice and in normal foot skin. DMXAA, when injected intraperitoneally in restrained non-anaesthetized animals, reduced tumour perfusion, as measured using the RbCl extraction procedure, and increased necrosis in histological section, but these effects were dependent on the drug dose and time interval. At a dose of 20 mg/kg, it significantly enhanced the thermal damage of this tumour, when given 1 h or more before the start of heating, as assessed by a tumour growth assay. This enhancement became larger with increasing interval between the two treatments. No thermo-potentiation was seen at doses of 10 mg/kg or lower. These combined effects seem to be associated with the tumour vascular shut-down by DMXAA. Thermal potentiation by DMXAA was also dependent on the heating temperature, with a greater enhancement relative to hyperthermia alone obtained at the lower temperatures at 40.5 and 41.5 degreesC than at the higher temperature of 42.5 degrees C. DMXAA (20 mg/kg) also enhanced the heat damage of normal skin, and this could not be explained by any DMXAA-induced TNF-alpha production. The heat enhancement-ratio by DMXAA was larger in tumours (1.9) than in normal skin (1.3-1.5), thus giving rise to a therapeutic gain.

Animals↗

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The effect of combining flavone acetic acid and hyperthermia on the growth of a C3H mammary carcinoma in vivo.

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Animals↗

PubMedDate not supplied

Studies of regional cerebral blood flow.

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Brain Injuries↗

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A paradoxical cerebral hemodynamic effect of hydralazine.

Hydralazine is shown to have a very complex cerebral hemodynamic effect. It raises the intracranial pressure which, together with its effect upon systemic blood pressure, reduces the cerebral perfusion pressure. In spite of this and a concomitantly induced hyperventilation by hydralazine, CBF increases with some delay. The conclusion is that hydralazine is a cerebral vasodilator acting immediately upon cerebral capacitance vessels but later upon the resistance vessels as well.

Adolescent↗

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Studies on fractionated hyperthermia in L1A2 tumour cells in vitro: response to multiple equal heat fractions.

The development of thermotolerance in L1A2 cells in vitro was investigated after fractionated hyperthermia at 42 degrees C. A single pretreatment of 90 min at 42 degrees C resulted in maximal thermotolerance at a 10 h fractionation interval with a thermotolerance ratio (TTR) of approximately 4.5. Thermotolerance was maintained at this level if the cells were exposed to 1-3 additional 90 min pretreatments separated by 10 h intervals. At a 6 h fractionation interval, where thermotolerance was still developing, additional 90 min pretreatments raised the level of thermotolerance to the level induced by the 10 h interval; the TTR increased from 2.1 to 4.5. Intervals of 20 and 24 h, at which there was decay but not complete disappearance of thermotolerance, did not induce such a build-up, and the TTR remained constant at 2.5 and 1.6, respectively. With 2 h fractionation intervals, where a single pretreatment did not induce thermotolerance, no thermotolerance was induced by additional pretreatments. With a shorter preheating time (e.g. 45 min at 42 degrees C) administration of a single pretreatment induced maximal thermotolerance after 6 h with a TTR of 3.0; additional 45 min pretreatments separated by 6 h intervals maintained this level. The thermotolerance induced by multifractioned hyperthermia as described above decayed in a similar way to that of cells exposed to a single pretreatment.

Animals↗

PubMedDate not supplied

Factors of importance for the development of the step-down heating effect in a C3H mammary carcinoma in vivo.

The effect of step-down heating (SDH) was investigated in a C3H mammary carcinoma inoculated into the feet of CDF1 mice. The SDH effect was evaluated by comparing slopes of time versus growth delay curves of SDH-heated with the curve for single-heated controls. The effect was quantified by a ratio: 'step-down ratio' (SDR), defined as slope (SDH-heated)/slope (single-heated). Step-down heating resulted in thermosensitization in contrast to step-up heating which did not affect the heat sensitivity. The kinetics of the step-down heating effect was investigated by inserting an interval between a 44.5 degrees C/10 min sensitizing treatment (ST) and a 42.0 degrees C test treatment (TT). The effect of SDH was maximal with no interval between ST and TT (SDR = 2.3), decayed within 2 h and turned into thermotolerance. This thermotolerance was maximal after 12 h and decayed within 120 h. The effect of varying the TT temperature was investigated in the range 39.0-44.5 degrees C (ST = 44.5 degrees C/10 min). Below 42.5 degrees C the SDR value increased exponentially, and even a 39 degrees C TT produced a significant heat damage. An Arrhenius analysis was made showing a straight line in the whole temperature range with an activation energy of 526 kJ/mol and an increased activation entropy. These data show that thermosensitization can be induced by SDH in C3H mammary carcinomas in vivo. The effect seems to decay within 2 h, and by decreasing the heat activation energies the effect of low temperature heating is increased.

Animals↗

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Some problems related to the clinical use of thermal isoeffect doses.

The well-known biological isoeffect relationship between treatment time and temperature has been suggested as a basis for a general biological heat dose unit which could be used to compare the effect of different heat treatment schedules. This is frequently expressed as 'equivalent heating time at 43 degrees C'. Such a conversion has in experimental studies been shown to be effective in comparing single heating schedules. However, clinical treatment has some features which may strongly influence the usefulness of an isoeffect heat dose. Firstly, the heat distribution is generally heterogeneous and fluctuates with time, which in some situations results in increased damage due to step-down heating. Secondly, in the situation where hyperthermia and radiation are given simultaneously, the time-temperature relationship may be different from that in the case of heat alone, and from the effect of heat given as an adjuvant to radiotherapy. Thirdly, most clinical treatments are given as fractionated treatments, and it is almost certain that thermotolerance may influence the biological heat effect to some extent. However, with the unknown kinetics of thermotolerance the magnitude of this phenomenon cannot be predicted. A series of experiments in a C3H mammary carcinoma were performed in order to analyse some of these problems.

Hot Temperature↗

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Hyperthermia as an adjuvant to radiotherapy in the treatment of malignant melanoma.

One hundred and fifteen cutaneous or lymph node metastases from malignant melanoma were treated with three fractions of irradiation alone in 8 days (62 tumours) or followed by heat either immediately (simultaneous treatment, 26 tumours) or after an interval of 3-4 h (sequential therapy, 27 tumours). In addition, three tumours were treated unsuccessfully with heat alone. The total doses of radiation varied between 15 and 30 Gy, allowing a dose-response analysis. For irradiation alone the isoeffective dose to obtain 50 per cent complete response (TCD50) was 26.3 Gy. Addition of heat reduced the TCD50 significantly (p less than 0.05) with a thermal enhancement ratio (TER) of 1.43 for simultaneous treatment and 1.24 for sequential therapy. Also the persistent local control at 18 months was improved by hyperthermia (56 per cent versus 86 per cent, p less than 0.05). However, simultaneous treatment also enhanced the acute skin response to the same extent as the tumour (TER 1.42 for severe erythema). This schedule thus gave no therapeutic gain. In contrast, no normal tissue enhancement was found after sequential treatment (TER 1.02). Such a treatment schedule resulted in a significantly improved therapeutic ratio of 1.22. This effect was especially prominent in larger tumours (if sufficiently heated) and an analysis corrected for volume showed a TER of 1.51. A special analysis was performed in patients with multiple lesions. 15 pairs of tumours were given the same radiation dose, with or without hyperthermia. Out of these, 11 showed a better response, three showed the same response, and only in one pair was the best response in the tumour obtained by radiation alone.

Combined Modality Therapy↗

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Hydralazine-induced enhancement of hyperthermic damage in a C3H mammary carcinoma in vivo.

Prolonged oxygen deprivation of cells in vitro or in vivo increases the sensitivity of those cells to heat. Hydralazine is a peripheral vasodilator, currently used clinically as an antihypertensive agent, which has been reported to be able to reduce tumour blood flow and increase the degree of tumour hypoxia. We have investigated the potential of hydralazine to enhance the response of a C3H mammary carcinoma to local hyperthermia. The tumour was grown in the foot of mice and its response to treatment assayed by regrowth delay. Our results show that a single intravenous injection of hydralazine (5 mg/kg) significantly enhances the heat damage produced by heating for various times at either 41.5, 42.5, or 43.5 degrees C. This effect was dependent on the time of starting to heat after hydralazine injection, with the greatest enhancement occurring when heat was given within 1 h following drug administration. However, the effect was independent of the hydralazine concentration, at doses above 2.5 mg/kg. Hydralazine also significantly decreased mean arterial blood pressure and the uptake of 86RbCl into tumours. Our results suggest that the observed heat sensitization was primarily a consequence of an increase in tumour hypoxia, probably resulting from a decrease in tumour blood perfusion.

Animals↗

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Step-down heating in a C3H mammary carcinoma in vivo: effects of varying the time and temperature of the sensitizing treatment.

The effect of step-down heating (SDH), consisting of an initial sensitizing treatment (ST) performed at either 44.5 degrees C or 43.5 degrees C followed by a lower temperature test treatment (TT), was investigated in a C3H mammary carcinoma in vivo. A linear relationship between heating time and tumour growth delay was observed for all temperature combinations applied. At a given TT temperature, SDH increased the slope of the dose-response curve compared to the curve for tumours, single-heated without an initial ST. The slope of the SDH curves increased asymptotically towards a plateau value as the ST time at 44.5 degrees C was increased. The time-temperature relationship for single heating was described by a biphasic Arrhenius curve with activation energies of 1361 +/- 34 and 666 +/- 54 kJ/mol below and above an inflection point at 42.5 degrees C, respectively. For SDH, the Arrhenius curve gradually became straight with increasing ST time, and the activation energy saturated at a value of 425 +/- 25 kJ/mol. The reduction of the activation energy at an ST temperature of 43.5 degrees C was due rather to the extent of ST heat damage than to the ST time or temperature used. These results may be relevant for calculations of thermal doses, since even a short temperature peak (e.g. 44.5 degrees C/5 min) significantly changed the time-temperature relationship.

Animals↗

PubMedDate not supplied

A comparison between the effect of step-down heating in a tumour and a normal tissue in vivo.

A comparison between the effect of step-down heating (SDH) obtained in a C3H mammary carcinoma grown in the feet of CDF1 mice and the skin of normal CDF1 feet is presented. Water-bath heating was used, and SDH was obtained by giving a 44.7 degrees C/10 min treatment followed by heating at 42.2 degrees C for variable times. Single heating at 42.2 degrees C and step-up heating (SUH), i.e. 42.2 degrees C followed by 44.7 degrees C/10 min, were used as controls. The endpoint was the heating time at 42.2 degrees C to obtain either a definite tumour growth time (TGT50) or a specific skin score level (RD50) in 50% of the animals. The effect of SDH and SUH was quantified by the step-down ratio (SDR), calculated as the ratio of the heating times at 42.2 degrees C to obtain the specific endpoint. In both assays the effect of SDH was seen as a significant left shift of the SDH dose-response curve compared to the curve for single heating and SUH. For the comparison of the tumour and the normal tissue response, damage levels with comparable heating times for single heating were used. The therapeutic effect was then investigated by calculating the therapeutic gain factor (TGF), where TGF = SDR(tumour)/SDR(normal tissue). Neither SUH nor SDH gave a TGF significantly different from 1. The results suggest that SDH may be used clinically to shorten the heating time without decreasing the therapeutic effect.

Animals↗

PubMedDate not supplied

Use of tetrahydraindazolone dicarboxylic acid (HIDA) to improve the therapeutic effect in vivo of combined cisplatin, heat and radiation treatment.

The effect of tetrahydraindazolone dicarboxylic acid (HIDA) on tumour response and mouse lethality after treatment with cisplatin given either alone or combined with hyperthermia (43.5 degrees C/60 min) with or without radiation, was studied in the CDF1 mouse bearing a foot transplanted C3H mouse mammary carcinoma. The tumour response to a combined heat, cisplatin and HIDA treatment was assessed by tumour growth time, while local tumour control was used when irradiation was added to that treatment scheme. Toxicity was estimated as lethality within 14 days. Cisplatin and heat exerted the highest antitumour effect when given simultaneously, but at the same time there was a substantial increase in lethality. No sensitization of the tumour response or enhanced toxicity to cisplatin was observed if heat was given sequentially (i.e. 4 h) after cisplatin. The effect of this sequential schedule being only additive. When HIDA (100 mg/kg) was given 150 min before cisplatin and tumours heated 15 min later, the lethal toxicity was significantly reduced. HIDA did not, however, influence tumour growth time results. In tumour control studies combining radiation, drug and heat, cisplatin (6 mg/kg) and heat (43.5 degrees C/60 min) were given simultaneously 4 h after local irradiating the leg of tumour-bearing mice. The lethality of this regime was more than 55%, but when HIDA was added to the protocol, the toxicity fell to 5% without affecting local tumour control. In conclusion, HIDA administered before cisplatin protects against drug-induced toxicity without reducing the drug's antitumour activity when used alone or in combination with hyperthermia and/or radiation, and thus results in a significantly improved therapeutic benefit.

Animals↗