[en] The aim of the twelve studies included in the present thesis was to determine the importance of hypoxia for various anti-neoplastic treatment modalities, and to evaluate possible ways of overcoming the hypoxia problem by combined modality therapy. The murine tumor systems were the C3H mammary carcinoma with 5-12% hypoxic cells, and the SCCVII squamous cell carcinoma with 2% hypoxic cells. The radiation response was significantly improved by the use of hypoxic cell radiosensitizers such as nimorazole or misonidazole, or by allowing the mice to breathe oxygen or carbogen during irradiation. In contrast, the radiation response was significantly impaired by carbon monoxide breathing at a level comparable to what has been observed in heavy smokers. The clamped TCD₅₀ assay was used to classify cancer chemotherapeutic drugs according to their preferential cytotoxicity towards the different tumor subpopulations. Methotrexate had no effect on hypoxic cells and was only borderline toxic towards aerobic cells. Three drugs had significant effect against oxic cells only (5-fluorouracil, bleomycin and cisplatin). Similarly, three drugs were toxic towards hypoxic cells only (etoposide, carmustine, and mitomycin c). Three drugs were effective towards both cell types (vincristine, adriamycin, cyclophosphamide). Hypoxic cells in areas with insufficient blood supply, poor nutrition and increased acidity is known to be highly sensitive to hyperthermia. In a study where cisplatin, heat and x-rays were given together, the local tumor control was not improved when compared to radiation + heat, apparently due to a lack of enhancement in the killing of hypoxic cells. These studies have demonstrated the influence of tumor oxygenation on tumor response to treatment with drugs, hyperthermia and irradiation. New strategies targeted also against perfusion-limited hypoxia is needed. One of the most important conclusions from the present thesis can be implemented without expensive trials or increased morbidity: Patients undergoing curative radiotherapy should quit smoking, since the increase in tumor hypoxia may lead to impaired local tumor control. (EG) (149 refs.)

[en] The variation in hypoxic fraction as a function of time after various priming doses of radiation has been investigated in a C3H mouse mammary carcinoma in situ. The hypoxic fraction was calculated from data for local tumor control. Untreated tumors were found to contain 4.8% radiobiologically hypoxic cells. Within minutes after a priming dose of 20 Gy given in air, the hypoxic fraction increased to a value not significantly different from 100%. After 4 h, reoxygenation was complete (hypoxic fraction 1.3%), and the hypoxic fraction stabilized at a level significantly below the untreated value. Following a priming dose of 40 Gy the reoxygenation pattern was different: The hypoxic fraction stayed above the pretreatment value for 4 h, and pronounced reoxygenation occurred after 12 h (hypoxic fraction 0.4%). At longer time intervals the hypoxic fraction again increased to--and slightly above--the oxygenation level of untreated tumors. The present findings show that reoxygenation in solid tumors is a function of radiation dose, and the data suggest that mechanisms other than a decrease in tumor cell O2 consumption are involved in tumor reoxygenation

[en] The radiosensitizing and cytotoxic properties of Mitomycin C (MMC) was investigated in vivo using regrowth delay and tumor control assays. MMC significantly enhanced the radiation-induced growth delay when administered 15 min before irradiation; the slope of the dose response curve significantly increased and corresponded to a Dose Modifying Factor (DMF) of 1.9 (1.5-2.3; p less than 0.001). When MMC was given 4 hr after irradiation, the additional regrowth delay resulted in a parallel shift of the dose response curve, and MMC was not significantly dose modifying (DMF 1.3 (0.9-1.3); p less than 0.05). From isobologram analysis it was found that the preirradiation MMC schedule resulted in supra-additive responses, whereas MMC given after irradiation had an additive effect. The enhancement of radiation-induced tumor control was similarly found to peak when MMC was given 6 hr to 15 min prior to irradiation. At these intervals, the observed TCD50 for the combined treatments relative to radiation alone corresponded to Enhancement Ratios of 1.27 and 1.29, respectively (p less than 0.001). Longer intervals between the modalities reduced the enhancement, but the combined treatments were still significantly better than radiation alone (ER 1.12, 1.16 and 1.17; p less than 0.001). The significant enhancement of tumor control correlated with a substantial drug-induced cytotoxic effect toward hypoxic tumor cells, as determined by clamped TCD50 experiments. A single dose of MMC (3 mg/kg) was found to kill up to 97% of all hypoxic tumor cells

[en] The effect of step-down heating (SDH) on the interaction between heat and radiation was investigated in a C3H mammary carcinoma in vivo. SDH consisted of an initial sensitizing treatment (ST) performed at 44.5^oC or 43.5^oC followed by a lower temperature test treatment (TT) in the range 41.0-43.0^oC. Step-up heating (SUH), i.e. TT followed by ST, and single heating were used as controls. The end-point was the radiation dose needed to control 50% of the tumours (TCD₅₀). The results were evaluated by calculating the thermal enhancement ratio (TER) defined as TER=TCD₅₀ (radiation alone)/TCD₅₀ (radiation and heat). For a simultaneous application of TT and radiation a significant enhancement of direct heat radiosensitisation was observed with increasing ST time to ST temperature using SDH. In contrast, only a minor increase was seen with SUH. A comparison between TCD₅₀ values for the corresponding SUH and SDH schedules revealed that the SDH effect was largest at 41.0-42.0^oC and decreased with increasing TT temperature. The radiosensitizing effect of SDH also decreased if an interval was allowed between ST and TT or between TT and radiation. However, as a result of an increase cytotoxicity towards hypoxic tumour cells, the TCD₅₀ value for SDH remained significantly smaller than for SUH. (author)

[en] In this note, maximum-likelihood estimation or 'direct analysis' is proposed for joint analysis of local control data from tumours treated in air or under clamped conditions. The multi-fraction versions of the linear-quadratic (LQ) and multi-target (MT) models are both fitted to a series of fractionated irradiations in a C3H mouse mammary carcinoma. Goodness-of-fit test statistics showed that whereas the deviations from the LQ model were statistically insignificant (p>·25), the MT model could be rejected for this data set (p approx = 0.005). A simulation study comparing direct analysis with a two-step analysis based on TCD₅₀ values showed a greater robustness of the direct approach, especially in the case of data from non-optimal experimental designs. (author)

[en] The present investigation has been carried out to evaluate the sensitivity of the inner ear to irradiation. Cochlear function was tested in a cohort of 22 patients before and 7-84 months after receiving external irradiation for nasopharyngeal carcinoma. The pre-irradiation sensori-neural hearing threshold at 500, 1000, 2000, and 4000 Hz was used as a baseline for the individual patient, and the observed sensori-neural hearing loss (SNHL) was calculated as the difference between pre- and post-irradiation values. The pre-irradiation hearing level or patient age was not correlated with the actual SNHL. In contrast, there was a significant correlation between the total radiation dose to the inner ear and the observed hearing impairment. SNHL was most pronounced in the high frequencies, with values up to 35 dB (4000 Hz) and 25 dB (2000 Hz) in some patients. The latent period for the complication appeared to be 12 months or more. The deleterious effect of irradiation on the hearing should be kept in mind both in treatment planning and in the follow-up after radiotherapy

[en] In this retrospective study the results of primary and salvage treatment of oropharyngeal carcinoma were evaluated. A total of 289 consecutive patients (103 females and 186 males) were included in the study. Most tumours originated in the tonsil area (58%) and comprised stages I 8%, II 19%, III 46% and IV 28%. The primary treatment was delivered with curative intent in 276 cases (96%). Of these, 266 received primary radiotherapy. The median radiation dose was 62 Gy, given as laterally opposed fields to the primary tumour and bilateral neck. Eight patients were treated with primary surgery and two with chemotherapy as part of a curatively intended treatment programme including radiotherapy. Six patients received palliative treatment, and seven were not treated at all. Out of 276 tumours treated with curative intent, 173 reappeared; 72% recurred in T position, 38% in N position, and 12% at distant metastatic sites, some in combination. Salvage surgery was possible in 52 patients, and 24 treatments were successful. Salvage radiotherapy or cryotherapy was used in 22 patients and 4 were controlled. For the entire group, the 5-year locoregional tumour control, disease-specific survival and overall survival rates were 38%, 44% and 31%, respectively. For patients treated with curative intent, clinical T- and N-stage, stage, tumour size, gender, age, and pretreatment haemoglobin were significant prognostic parameters in a univariate analysis. The Cox multivariate analysis showed that T-stage, N-stage and gender were independent prognostic factors. It is concluded that T-stage, N-stage and gender are significant independent prognostic factors. The primary control of the carcinoma in the T-position is crucial for overall success, but salvage surgery is found to have a favourable success rate in patients suitable for relapse treatment

[en] Patients who receive radiotherapy for head and neck cancer are likely to develop painful mucositis. The pain is characterized by a burning or stinging sensation similar to neuropathic pain sensations. The purpose of the present study was to compare the analgesic effect of a tricyclic antidepressant (TC), commonly used in the treatment of neuropathic pain, with the effect of opioids on radiation-induced mucositis pain. Forty-three patients receiving 66-68 Gy external radiation according to the DAHANCA guidelines (the Danish Head and Neck Cancer Study Group) were randomized to either morphine or TC when mucositis pain was insufficiently managed with weak analgesics. Patients with insufficient pain control in either treatment arm received supplementary medication from the opposite treatment arm. Pain was evaluated weekly using a VAS scale and the McGill Pain Questionnaire. The degree of mucositis and the degree of depression were measured at the same time intervals. Twenty-two patients entered the opioid arm and 21 the TC arm. Two patients in each arm were non-evaluable. VAS pain scores were significantly reduced in the opioid treatment arm one week after randomization (p=0.01). Eight patients in the TC arm were managed with TC alone, but for 11 patients it was necessary to add morphine. The 20 evaluable patients in the morphine arm required no additional treatment. There were no significant differences in side effects between the two groups. Higher pain scores in the TC arm, but not in the opioid arm, were significantly correlated with higher BDI scores. Some head and neck cancer patients with radiation-induced nucositis pain may have sufficient pain control on TC alone. This might be useful in patients with relative counter-indications to opioid treatment

[en] From the checking of 2750 index cards of hazards, the study relates the distribution of the chemical hazards in the Centre d'Etudes Nucleaires of Fontenay-aux-Roses. Those concerning the greatest number of agents in the Centre are classified according to the categories corresponding to the different conditions of working. Thus, the most important are put forward. Then, the authors rapidly make a review of hazards which may have some special interest because they appear more specific of the nuclear energy or because they are the most frequently noted on the index cards of hazards. The case of the tributylphosphate is studied more precisely. (authors)

[en] The aim of this study was to evaluate the results of the initial and salvage treatment for hypopharyngeal carcinoma. The study was conducted in 1963 to 1991 and included 138 patients (38 females and 100 males). Most of the tumours originated in the piriform sinus (86%). Tumour stage distribution was T1: 20%, T2: 27%, T3: 37% and T4: 17% and nodal stage distribution was N0: 45%, N1: 25%, N2: 10%, and N3: 20%. Primary treatment was delivered with curative intent in 124 out of 138 cases. Treatment failure was noted in 98 patients, with 55% recurrence in T-position, 39% in N-position, and 14% at distant metastases sites. Salvage surgery was successful in 9 out of 32 patients. The overall 5-year locoregional tumour control, cause-specific and overall survival rates were 20%, 25% and 19%, respectively. Univariate actuarial analysis showed that T- and N-stage, clinical stage, tumour size and well-differentiated tumours were significant prognostic parameters. A Cox multivariate analysis showed that only the T- and N-stages were independent prognostic factors. In conclusion, the prognosis for advanced hypopharyngeal carcinoma is extremely poor and the meagre results with conventional radiotherapy alone indicate that other treatment modalities should be introduced in the management of this disease