Glioma cell interactions with fetal rat brain aggregates in vitro and with brain tissue in vivo.

Two malignant rat neurogenic cell lines have been confronted with reaggregation cultures of fetal rat brain in a stationary culture system. In this organ culture system several morphological aspects of the developing brain are imitated. The malignant cell lines showed invasive and progressive growth into the brain tissue, ending with a completely destroyed aggregate within 10 days of coculture. One cell line (BT5C) showed solid invasion with groups of cells replacing different layers of the brain tissue. A considerable degree of normal cell lysis was seen, both at the edge of invasion and at distant parts of the aggregate. This cell line seemed to activate macrophages in the aggregates. In addition, conditioned medium from these cultures caused degeneration of the brain aggregates. The other cell line (BT4Cn) showed invasion by single cells where the replacement and destruction of the tissue was not accompanied by distant lysis. Both cell lines showed the same pattern of invasion in vitro as was seen in the brains of isogeneic animals in vivo, showing that the individual tumor characteristics were also reflected during invasive growth in organ culture.

Immunolocalization of extracellular matrix proteins during brain tumor invasion in BD IX rats.

The distribution of several native extracellular matrix proteins (type I, III, and IV collagens and fibronectin) using immunofluorescent localization is described for in two different malignant gliomas (BT4A and BT4An). In addition, antibodies against denatured forms of type I and III collagens were used to localize areas of active degradation within the tumors. We have shown that both tumors express the native connective tissue components studied, although the distribution of these components within and between the tumors was different. In addition, native type I and III collagens and fibronectin were overexpressed in the tumors compared to the normal brain. Morphometry on immunostained type IV collagen sections showed an increase in vascular elements in both tumors compared to normal brain tissue. The BT4A tumor, which by light microscopy showed a degradative mode of invasion, expressed denatured type I and III collagens at the tumor-brain border zone, suggesting that this tumor has collagenolytic activity. The present article suggests that the distribution and changes in extracellular matrix protein synthesis and degradation may play an important role in the progressive growth of brain tumors in vivo.

Knowledge of and attitudes toward complementary and alternative therapies; a national multicentre study of oncology professionals in Norway.

This study reports on oncology professionals' knowledge and attitude toward complementary and alternative medicines (CAM), classified according to their primary application as complementary or alternative methods. In June 2002, we conducted a national, multicentre survey of 828 Norwegian oncologists, nurses, clerks and therapeutic radiographers. A response rate of 61% was achieved. Only a few physicians (4%) described their reactions to alternative medicine as positive compared with nurses (33%), therapeutic radiographers (32%) and clerks (55%) (P<0.0001). Females showed a more positive view than males (33% versus 14%, P<0.0001). More participants expressed a positive attitude to complementary versus alternative medicines. Most respondents regarded healing by hand or prayer, homeopathy, and Iscador (mistletoe) as alternative therapies. In contrast, most respondents classified acupuncture, meditation, reflexology, music/art-therapy, aromatherapy and massage as complementary therapies. This survey demonstrates major differences, by gender as well as oncology health profession in views about and the classification of various CAM methods.

Effect of sodium nitroprusside-induced hypotension on the blood flow in subcutaneous and intramuscular BT4AN tumors and normal tissues in rats.

PURPOSE: To examine the effect of infusion of the vasodilator sodium nitroprusside (SNP) on the blood flow in normal tissues and BT4An tumors growing subcutaneously or intramuscularly in BD IX rats. METHODS AND MATERIALS: Sodium nitroprusside was given as a continuous intravenous infusion to keep the mean arterial pressure stable at 60 mmHg. The cardiac output, organ blood flow, and perfusion of the BT4An tumors were measured by injection of radiolabelled microspheres at control conditions and after 20 min SNP infusion in each animal. Two series of experiments were performed with two anesthetics with different mechanisms of action, Inactin and the midazolam-fentanyl-fluanisone combination (MFF), to secure reliable conclusions. RESULTS: Cardiac output, heart rate, and blood flow to the skeletal muscles, heart, and liver increased during SNP infusion in either anesthetic group. In the kidneys and particularly the skin, decreased blood flow by SNP was observed. When located subcutaneously on the foot, the blood flow in the tumor fell to 23.4% and 21.4% of the control values in the MFF- and Inactin-anesthetized animals, respectively. This was accompanied by a similar fall in the blood flow in the foot (tumor bed) itself. In the intramuscular tumor, the blood flow fell to 24.8% of the control value in the MFF group, whereas the corresponding figure was 36.2% in the Inactin group. In the surrounding muscle (tumor bed) the blood flow increased significantly, most pronounced in the MFF experiment, where it was tripled. CONCLUSION: The fall in the tumor perfusion by SNP may be exploited therapeutically to increase the tumor temperature during hyperthermia. Predominant heating of the tumor compared to the tumor bed can be expected if the tumor is growing in or near skeletal muscles.

Use of the vasodilator sodium nitroprusside during local hyperthermia: effects on tumor temperature and tumor response in a rat tumor model.

PURPOSE: The effect of a decrease in the mean arterial blood pressure (MAP) induced by sodium nitroprusside (SNP) on the tumor temperature during hyperthermia (HT), and on the cytotoxic effect of HT, was studied in the BT4An tumor transplanted to the hind limb of BD IX rats. Experiments with two different anesthetics, pentobarbital and the midazolam/fentanyl/fluanisone combination (MFF), were performed to secure reliable conclusions. METHODS AND MATERIALS: In the tumor response experiments local waterbath HT at 44.0 degrees C was given for 60 min. Sodium nitroprusside was administered as a continuous intravenous infusion to lower the MAP to 60 or 80 mmHg during HT. In two other experiments the temperature at the base of the tumor during HT was measured before and during SNP infusion. In animals without tumor the temperature was measured subcutaneously on the foot during HT with or without SNP-induced hypotension. RESULTS: When SNP was given to lower the MAP to 60 mmHg during HT in MFF anesthetized animals, the median tumor growth time (TGT) was 70 days, compared to 14.5 days in the HT alone group. The corresponding figures were 127 and 12.1 days with pentobarbital anesthesia. In the HT + SNP group, more than 40% cure was observed in both experiments. No cures were seen in any of the other groups. Hyperthermia alone prolonged the TGT slightly, whereas SNP given alone had no effect, compared to controls. When the MAP was lowered to 80 mmHg by SNP infusion during HT (MFF anesthesia), the median TGT was 19.9 days, which was significantly longer than that in the HT alone group (10.9 days). In the MAP range from 60 to 120 mmHg, a nearly linear relationship between the MAP and the tumor temperature was found during HT in MFF anesthetized animals. With both anesthetics, the median temperature at the base of the tumor was about 0.8 degrees C higher during HT when the MAP was lowered to 60 mmHg by SNP. In animals without tumors, the temperature subcutaneously on the foot was 0.3 and 0.4 degrees C higher during SNP infusion in the MFF and pentobarbital group, respectively. CONCLUSION: We have developed a small animal model in inbred rats feasible for exploring the influence of a stable blood pressure reduction induced by SNP, on the effect of HT given alone or in combination with other treatment modalities to a transplantable tumor. The greatly increased cytotoxic effect of local waterbath HT in the present tumor response experiments is probably a consequence of increased tumor temperature during SNP infusion.

Thermochemotherapy with cisplatin or carboplatin in the BT4 rat glioma in vitro and in vivo.

The effect of thermochemotherapy with cisplatin or carboplatin was compared in the BT4-cell line. In vitro: BT4C-cells were treated with different concentrations of cisplatin or carboplatin, with or without simultaneous hyperthermia. In vivo: Inbred BD IX rats with transplanted glioma-like BT4A or glioblastoma-like BT4An tumors on the hind leg were treated with cisplatin (4 mg/kg) or carboplatin (50 mg/kg), with or without local hyperthermia. In vitro the benefit of adding hyperthermia to chemotherapy was similar for cisplatin and carboplatin. For both cisplatin and carboplatin, the difference of treatment effect between thermochemotherapy and chemotherapy alone increased with higher drug concentrations. In vivo hyperthermia clearly enhanced the effect of carboplatin on BT4A tumors. When treating BT4An tumors, thermochemotherapy with cisplatin or carboplatin was equally effective. Both combinations were superior to treatment with hyperthermia alone. Local toxicity and weight loss following thermochemotherapy were comparable when substituting cisplatin with carboplatin.

Timing of hypertonic glucose and thermochemotherapy with 1-(4-amino-2-methylpyrimidine-5-yl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) in the BT4An rat glioma: relation to intratumoral pH reduction and circulatory changes after glucose supply.

PURPOSE: Intraperitoneal hypertonic glucose has previously been shown to induce hyperglycemia, hemo-concentration, and to influence systemic and tumor circulation, and, thus, enhance the effect of thermochemotherapy with 1-(4-amino-2-methylpyrimidine-5-yl)methyl-3-(2-chloroethyl)-3-nitrosoure a (ACNU) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). However, the optimal timing and the precise mechanisms responsible are not known. The effect of different time intervals between glucose load and thermochemotherapy with ACNU in the treatment of BT4An tumors, therefore, was investigated. Changes of serum glucose (Se-glucose), hemoglobin, systemic circulation parameters, tumor pH, and tumor temperature, induced by intraperitoneal glucose and/or hyperthermia, were measured to assess their effect on tumor growth. METHODS AND MATERIALS: (a): Inbred BD IX rats with BT4An tumors on the hind leg were treated with ACNU 7 mg/kg intravenously just before waterbath hyperthermia, and intraperitoneal hypertonic glucose (6 g/kg) at different time intervals before (240-0 min) or immediately after thermochemotherapy. (b): Intratumoral pH and temperature were measured at different intervals after intraperitoneal glucose, and during hyperthermia with or without previous glucose. (c): Hemoglobin, hematocrit, and Se-glucose were measured at different times after intraperitoneal glucose. (d): Mean arterial pressure, pulse pressure, and heart rate were measured for 120 min after intraperitoneal glucose. RESULTS: (a): The number of tumor controls and the growth delay was greatest with glucose 45 min before thermochemotherapy, and least with a time interval of 240 min. Glucose after thermochemotherapy delayed tumor growth. (b): After intraperitoneal glucose alone, intratumoral pH decreased gradually from 6.76 to 5.86 after 240 min. Hyperthermia 120 min after glucose induced a rapid further pH drop, while hyperthermia alone had no significant influence on pH. Intratumoral temperature was higher during hyperthermia in animals given glucose. (c): A substantial rise of Se-glucose and hemoglobin developed. The hemoconcentration was maintained also after reduction of Se-glucose towards normal values. (d): An initial tachycardia, and a reduction of the mean arterial pressure of about 10% 5-45 min after was measured. CONCLUSION: The data indicate that a complex interaction between gradually reduced tumor pH, hyperglycemia, hemoconcentration, and reduced tumor blood flow, and not a breakdown of systemic circulation, is responsible for the effect of intraperitoneal glucose on thermochemotherapy with ACNU. Interestingly, enhancement of thermochemotherapy effect was also seen when intraperitoneal glucose was given after heat and ACNU.

The new tubulin-inhibitor combretastatin A-4 enhances thermal damage in the BT4An rat glioma.

PURPOSE: To investigate the toxicity of combretastatin A-4 disodium phosphate (CA-4) and its vascular effects in the subcutaneous (s.c.) BT4An rat glioma, and additionally, to determine the tumor response of CA-4 combined with hyperthermia. METHODS AND MATERIALS: For assessment of drug toxicity, rats were given 50, 75, or 100 mg/kg CA-4 and followed by daily registration of weight and side effects. Interstitial tumor blood flow was determined by laser Doppler flowmetry in rats injected with 50 mg/kg CA-4. In the tumor response study we administered CA-4 50 mg/kg alone or combined with hyperthermia (waterbath 44 degrees C for 60 min) 0 or 3 h later. RESULTS: We found that CA-4, at a well-tolerated dose of 50 mg/kg, induced a considerable time-dependent decrease in the tumor blood flow. Tumor blood flow was reduced by 47-55% during the first 110 min after injecting CA-4, and thereafter remained decreased until the measurements were terminated. Administering CA-4 3 h before hyperthermia yielded the best tumor response and increased tumor growth time significantly compared with simultaneous administration of CA-4 and hyperthermia (p = 0.03). Interestingly, CA-4 alone did not influence tumor growth. CONCLUSION: CA-4 induces a gradual reduction in tumor blood flow which can be exploited to sensitize the BT4An tumor for hyperthermia.

Hyperthermia enhances mitoxantrone cytotoxicity on human breast carcinoma and sarcoma xenografts in nude mice.

In this preclinical in vivo study, we measured antitumor response, local side effects and systemic toxicity of locally applied water-bath hyperthermia given alone or simultaneously with mitoxantrone (3 mg/kg b.w. i.v.; LD 10) on a human derived breast carcinoma (MX 1) or a human sarcoma (S 117) transplanted to female athymic (nude) mice. A single hyperthermia treatment at a tumor temperature up to 43 degrees C for 1 hr caused in both tumor lines only minor tumor regressions and transient tumor growth delay. However, the antitumor effect of mitoxantrone was significantly enhanced by local hyperthermia at 42 degrees C and particularly at 43 degrees C. In both tumor lines complete tumor regressions were achieved only if mitoxantrone was combined with hyperthermia. Undesired side effects and drug toxicity were not enhanced by hyperthermia. According to in vitro data and the results of the present in vivo study mitoxantrone seems to be a good candidate for clinical trials in combination with locoregional hyperthermia.

Combretastatin A-4 and hyperthermia;a potent combination for the treatment of solid tumors.

BACKGROUND AND PURPOSE: Attacking tumor vasculature is a promising approach for the treatment of solid tumors. The tubulin inhibitor combretastatin A-4 disodium phosphate (CA-4) is a new vascular targeting drug which displays a low toxicity profile. We wanted to investigate how CA-4 influences tumor perfusion in the BT4An rat glioma and how the vascular targeting properties of CA-4 could be exploited to augment hyperthermic damage towards tumor vasculature. MATERIAL AND METHODS: We used the (86)RbCl extraction technique to assess how CA-4 influences tumor perfusion, and the tumor endothelium was examined for morphological changes induced by the drug. We combined CA-4 (50 mg/kg i.p.) with hyperthermia (44 degrees C, 60 min) at different time intervals to evaluate how therapy should be designed to affect tumor growth, and we studied the tumors histologically to assess tissue viability. RESULTS: We found that CA-4 induced a profound, but transient reduction in tumor perfusion 3-6 h postinjection. If hyperthermia was administered 3-6 h after injecting CA-4, massive hemorrhagic necrosis developed, and tumor response was significantly enhanced compared to simultaneous administration of the two treatment modalities (P<0.005). CA-4 alone had no influence on tumor growth and failed to disrupt the vasculature of the BT4An solid tumors. Interestingly though, a mild endothelial edema was observed in some tumor areas 3 h after injecting CA-4. CONCLUSIONS: We conclude that the combination of CA-4 and hyperthermia is a potent therapeutic option for BT4An tumors, but the selection of adequate time intervals between CA-4 and hyperthermia are imperative to obtain tumor response.

Tumor vasculature is targeted by the combination of combretastatin A-4 and hyperthermia.

BACKGROUND AND PURPOSE: Combretastatin A-4 disodium phosphate (CA-4) enhances thermal damage in s.c. BT(4)An rat gliomas. We currently investigated how CA-4 and hyperthermia affect the tumor microenvironment and neovasculature to disclose how the two treatment modalities interact to produce tumor response. METHODS: By confocal microscopy and immunostaining for von Willebrand factor, we examined the extent of vascular damage subsequent to CA-4 (50 mg/kg) and hyperthermia (waterbath 44 degrees C, 60 min). The influence on tumor oxygenation was assessed using interstitial pO(2)-probes (Licox system) and by immunostaining for pimonidazole. We examined the direct effect of CA-4 on the tumor cell population by flow cytometry (cell cycle distribution) and immunostaining for beta-tubulin (cytoskeletal damage). RESULTS: Whereas slight vascular damage was produced by CA-4 in the BT(4)An tumors, local hyperthermia exhibited moderate anti-vascular activity. In tumors exposed to CA-4 3 h before hyperthermia, massive vascular damage ensued. CA-4 reduced the pO(2) from 36.1 to 17.6 mmHg (P=0.01) in the tumor base, and tumor hypoxia increased slightly in the tumor center (pimonidazole staining). Extensive tumor hypoxia developed subsequent to hyperthermia or combination therapy. Despite a profound influence on beta-tubulin organization in vitro, CA-4 had no significant effect on the cell cycle distribution in vivo. CONCLUSION: Our results indicate that the anti-vascular activity exhibited by local hyperthermia can be augmented by previous exposure to CA-4.

Enhanced effect of combined hyperthermia and chemotherapy (bleomycin, BCNU) in a neurogenic rat tumour (BT4A) in vivo.

The neurogenic rat tumour BT4A was serially transplanted to the dorsum of the right hind leg of BD IX rats. The tumours were treated with water bath heating at 44.0 degrees C for one hour alone or combined with bleomycin or BCNU, both given intraperitoneally at a dose of 20 mg/kg. Bleomycin alone had no effect on tumour growth. Hyperthermia or BCNU alone both caused a transient growth delay before regrowth. Combination of hyperthermia and bleomycin caused a significantly enhanced effect with 8 partial regressions in 9 tumours. BCNU and hyperthermia resulted in 9 complete and one partial regressions of 10 treated tumours. Eight of these were cured. We conclude that the antitumour effects as well as the side effects caused by the combination of local hyperthermia and systemic administration of BCNU and bleomycin deserve further investigation.

Timing of combined hyperthermia and 1,3-bis(2-chloroethyl)-1-nitrosourea or cis-diamminedichloroplatinum in BD IX rats with BT4A tumours.

Groups of 7-10 evaluable BD IX rats with the neurogenic BT4A tumour on the right hind leg were treated with waterbath hyperthermia (44 degrees C, 60 min) in combination with 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) 20 mg/kg or cis-diamminedichloroplatinum (cis-DDP) 3 mg/kg i.p. at different sequences and timing within +/- 24 hr. Tumour responses were evaluated by tumour doubling time and clinical criteria, toxicity by toxic deaths, weight loss, and local skin reactions. With both BCNU and cis-DDP, tumour response was markedly dependent on timing; the greatest effects were obtained giving hyperthermia just after the drug. Local side effects were not different in the timing groups, but cis-DDP general toxicity was most severe when cis-DDP was given just before hyperthermia.

Hyperthermia or BCNU alone and combined in BD IX rats with BT4An tumours. Effects of a single or two equal fractions at different intervals.

BD IX rats with BT4An tumours subcutaneously on the hind leg were stratified after tumour size and treated by single dose 44 degrees C water bath hyperthermia for 90 minutes or with two 45 minute sessions at 24, 48 or 168 hour intervals. Other groups were treated by single dose BCNU at 20 mg/kg or by two divided doses at the same intervals, or by combined hyperthermia and drug as single treatment or as divided treatments at the same intervals. Intratumoural temperatures in some animals were carefully scanned for minimal temperature during two hyperthermia sessions 24 hours apart. Tumour response, normal skin damage and weight was evaluated. It was concluded that single dose hyperthermia and combined treatment yielded the best effect, but also resulted in the most severe skin reaction and weight loss. Hyperthermia was least effective at a 24 hour interval, indicating thermotolerance to be greatest at this time. The minimum intratumoural temperatures were higher at the second heat dose given at 24 hours, demonstrating a poorer ability to dissipate heat after the first treatment. The tumours were only slightly sensitive to BCNU alone, and no optimal schedule was found. BCNU increased the hyperthermia effect at all schedules, except for the 168 hour interval. The skin reaction to single dose hyperthermia was enhanced by BCNU.

CT and MR imaging features of primary central nervous system lymphoma in Norway, 1989-2003.

BACKGROUND AND PURPOSE: Studying imaging findings of non-acquired immunodeficiency syndrome (AIDS) primary central nervous system lymphoma (PCNSL), we hypothesized that the imaging presentation has changed with the increasing incidence of PCNSL and is related to clinical factors (eg, time to diagnosis and the patient's being diagnosed alive or at postmortem examination). MATERIALS AND METHODS: Chart and histologic reviews of patients recorded as having PCNSL during 1989-2003 in the Norwegian Cancer Registry identified 98 patients with non-AIDS PCNSL; 75 had available imaging. CT and MR images from the first diagnostic work-up after onset of symptoms but before histologic diagnosis were reviewed. RESULTS: CT and/or MR imaging in the 75 patients revealed no lesion in 10 (13%), a single focal lesion in 34 (45%), multiple focal lesions in 26 (35%), and disseminated lesions in 5 (7%) patients. All together, we identified 103 focal lesions (single/multiple): 63% in white matter, 56% abutting the ventricular surface, and 43% in the frontal lobes); 100% (102/102 lesions evaluated with contrast) showed contrast enhancement. The median time from imaging to diagnosis for patients with no, single, multiple, or disseminated lesions was 32, 3, 5, and 3 weeks, respectively (P = .01). Patients with no or disseminated lesions were more often diagnosed at postmortem examination (P = .06). Imaging findings were practically unchanged during the consecutive 5-year periods. CONCLUSIONS: White matter periventricular contrast-enhancing single or multiple focal lesions were typical of non-AIDS PCNSL. No or disseminated lesions heightened the risk of delayed or postmortem diagnosis. Although the incidence of non-AIDS PCNSL has increased, its presentation at imaging remains unchanged.

Combined hyperthermia and cis-diamminedichloroplatinum in BD IX rats with transplanted BT4A tumours.

Effects on tumours and toxicity of locally applied waterbath hyperthermia (44 degrees C, 60 min) and cis-diamminedichloroplatinum (cis-DDP) were investigated in BD IX rats with transplanted BT4A tumours on the hind foot. The effect of cis-DDP at doses of 2, 3 and 4 mg/kg measured as tumour growth time, defined as time to reach five times the tumour volume at treatment, increased in a drug dose-dependent manner by using hyperthermia. Moderate systemic hyperthermia at a mean of 41 degrees C during the second half of the treatment also increased the tumour regrowth delay of cis-DDP. Skin reactions after local hyperthermia did not increase in this cis-DDP dose range, but systemic toxicity of the drug was markedly enhanced by hyperthermia. At histological evaluation, hyperthermia at 44 degrees C resulted in marked vasodilatation, red blood cell pooling and haemolysis, with a seemingly almost complete central tumour perfusion shutdown lasting up to five days after treatment. The combination of cis-DDP and hyperthermia resulted in additional cell death especially at the tumour periphery and at depth near the tendon and muscle. This in vivo study confirms in vitro data indicating cis-DDP as a candidate for clinical trials combined with hyperthermia. As both the tumour and systemic side effects of cis-DDP are enhanced by hyperthermia, caution is advocated when applying high drug doses with systemic hyperthermia.

Fractionated hyperthermia in vivo: thermotolerance, sensitivity to BCNU and thermochemosensitivity in the BT4An rat glioma.

Although hyperthermia has been shown to increase the effect of some cytotoxic drugs both in vitro and in vivo, there is sparse data on the interaction of the two modalities during fractionated treatment in vivo. In vitro data suggest that, parallel to development of thermotolerance, tumour cell sensitivity to drugs may be modified. Thermotolerance in tumour and surrounding normal tissue and the sensitivity to the alkylating agent BCNU given alone i.p., or as thermochemotherapy, was investigated in the subcutaneously transplanted BT4An rat glioma. Tumours treated by 44 degrees C water bath hyperthermia alone minutes after the priming hyperthermia were initially sensitive to hyperthermia, but decreased heat sensitivity developed during continued heating. Thermotolerance in the skin was greatest at 24 h. When the skin reaction was compared with the effect on tumours, a therapeutic gain using hyperthermia alone was seen at 168 h. Tumours were most sensitive to BCNU just after the priming hyperthermia, least sensitive at 48 h. When thermochemotherapy with BCNU was given at different intervals after priming hyperthermia, an interaction between the modalities was seen, with the greatest tumour effect just after priming (six of 12 tumours controlled). At 24 h the summary effect of priming treatment and subsequent thermochemotherapy was not greater than thermochemotherapy treatment alone. The thermochemotherapy effect on tumours was more dependent on the hyperthermia sensitivity, i.e. thermotolerant state, than the sensitivity to BCNU alone at that time.

Referee: hyperthermia alone or combined with cisplatin in addition to radiotherapy for advanced uterine cervical cancer.

There are two evidence based therapeutic options for locally advanced cervical cancer: Radiotherapy and concurrent chemotherapy (cisplatin alone or combined with other drugs) or radiation and hyperthermia, documented in randomised trials. The weight of evidence is less for the most advanced stages. Combination of all three options are currently tested in several centres with good clinical response and acceptable toxicity. Based on a pragmatic approach we propose to proceed with a trial selecting cisplatin concurrent with radiation therapy as the standard arm to be compared with the same regimen with the addition of hyperthermia once a week.