[en] PURPOSE/OBJECTIVE: Several uncontrolled studies suggest that total treatment time (TTT) might be a highly significant prognostic factor in treatment outcome for patients with advanced cervix cancer (Girinsky et al, 1993). A prospective trial with bulky carcinomas of the cervix suggest that combined with brachytherapy, hyperfractionated radiotherapy (HFX) at total parametrial doses 10% above those used with standard fractionation (STD) was tolerated and at least as effective as STD (Komaki et al, 1994). The aim of our pilot study with accelerated HFX was to shorten the TTT by 14 days and to decrease late toxicity by lowering the dose per fraction. MATERIALS and METHODS: From August 1993 through January 1995, 21 patients (pts) with cervix cancer (IIb-IVa) were definitively treated with accelerated HFX as a concomitant boost (x,H). Combined external beam (EBRT, X15) and intracavitary high dose rate (HDR) brachytherapy (ICRT) was given within a TTT of 38 days and a total physical dose of 74.4 Gy at point A and 67.2Gy at point B (involved side). In comparison to our standard protocol (STD, 1985-92) the TTT was about 14 days shorter and the total dose about 12% higher. The treatment schedule now was: All patients were treated in a prone position on a belly board to displace the small bowel out of the pelvis during EBRT. The use of an indwelling intrauterine tube made only one general anesthesia necessary before ICRT. RESULTS: The procedure is simple, reproducible and also comfortable for the patient. All patients were treated within 40 days TTT. Tumor regression was similar to the STD. The acute side effects during treatment were mild and less frequent than with STD. Cystoscopy and proctoscopy (immediately and 6 weeks after treatment) showed that acute rectal side effects were minimal. Up to now no grade III or IV (RTOG scale) late effects developed. CONCLUSIONS: After feasibility has been proven a randomized phase III study was started. Endpoints are the 5-year survival and local control rates, which are expected to be about 15% better than with STD

[en] A one-step optimization method based on a least squares fit of the linear quadratic model to quantitative tissue response data after fractionated irradiation is proposed. Suitable end-points that can be analysed by this method are growth delay, host survival and quantitative biochemical or clinical laboratory data. The functional dependence between the transformed dose and the measured response is approximated by a polynomial. The method allows for the estimation of the alpha/beta ratio and its confidence limits from all observed responses of the different fractionation schedules. Censored data can be included in the analysis. A method to test the appropriateness of the fit is presented. A computer simulation illustrates the method and its accuracy as examplified by the growth delay end point. A comparison with a fit of the linear quadratic model to interpolated isoeffect doses shows the advantages of the direct method. (orig./HP)

[en] The objective of this study was to measure the effect of fractionation and total dose on the growth of two xenograft lines of high-grade human gliomas. Two astrocytomas (grades III-IV) were directly established as serially regraftable xenograft lines from the fresh explant to immunodeficient outbred nu/nu mice with a NMRI background. The radiation sensitivity of the tumours in single-time irradiation was measured in pilot studies and the doses for the fractionated irradiation series were determined subsequently. The results of the fractionation experiments and the repair processes observed therein are presented and discussed. (orig./MG)

[en] Spheroids grown from the human cell line EF8 of a lung metastasis of a human malignant fibrous histiocytoma were given fractionated irradiation with 60Co gamma rays at passages 31 and 32. The mean diameter of the spheroids at the time of treatment was 250 microns. Growth delay was used as the end point in these studies. Two experiments were carried out to determine the capacity and kinetics of repair of sublethal damage. In the first experiment, one, two, and five fractions were given at three or four dose levels with fixed intervals of 360 min. In the second experiment, schedules with two and four dose fractions and intervals of 0, 20, 60, 120, and 360 min were used, each at two dose levels. Data analysis was performed by a direct method based on the alpha/beta model and first-order repair kinetics of radiation damage. In both experiments, the alpha/beta value of EF8 spheroids was estimated to be about 8 (6-10) Gy. The rate constant of repair, mu, and its 95% confidence interval were estimated to be 0.62 (0.40-0.84) 10(-2) min-1, equivalent to a half-time of repair (T1/2) of 112 (83-172) min. A more detailed analysis of the data of the second experiment revealed a significant dependence of the rate constant of repair, mu, on the total radiation effect induced by the fractionated radiation treatments with short overall times. With increasing level of effect, mu decreased. These data indicate that the half-time of recovery of a human tumor can be longer than that of the surrounding normal tissue, in this case lung, at least for a limited range of doses and for some fractionation schedules

[en] The response to irradiation of five human xenograft cell lines - a malignant paraganglioma, a neurogenic sarcoma, a malignant histiocytoma, a primary lymphoma of the brain, and a squamous cell carcinoma - were tested in nude mice. All mice underwent 5 Gy whole body irradiation prior to xenotransplantation to minimize the residual immune response. The subcutaneous tumors were irradiated at a tumor volume of 120 mm³ under acutely hypoxic conditions with single doses between 8 Gy and 80 Gy depending on the expected radiation sensitivity of the tumor line. Endpoints of the study were the tumor control dose 50% (TCD₅₀) and the regrowth delay endpoints growth delay, specific growth delay, and the tumor bed effect corrected specific growth delay. Specific growth delay and corrected specific growth delay at 76% of the TCD₅₀ was used in order to compare the data to previously published data from spheroids. The lowest TCD₅₀ was found in the lymphoma with 24.9 Gy, whereas the TCD₅₀ of the soft tissue sarcomas and the squamous cell carcinoma ranged from 57.8 Gy to 65.6 Gy. The isoeffective dose levels for the induction of 30 days growth delay, a specific growth delay of 3, and a corrected specific growth delay of 3 ranged from 15.5 Gy (ECL1) to 37.1 Gy (FADU), from 7.2 Gy (ENE2) to 45.6 Gy (EPG1) and from 9.2 Gy (ENE2) to 37.6 Gy (EPG1), respectively. The corrected specific growth delay at 76% of the TCD₅₀ was correlated with the number of tumor rescue units per 100 cells in spheroids, which was available for three tumor lines, and with the tumor doubling time in xenografts (n = 5). The TCD₅₀ values corresponded better to the clinical experience than the regrowth delay data. There was no correlation between TCD₅₀ and any of the regrowth delay endpoints. This missing correlation was most likely a result of large differences in the number of tumor rescue units in human xenografts of the same size

[en] Published in summary form only

[en] The effects of tissue damage associated with invasive pO₂ measurements on radiation sensitivity were investigated using a xenografted squamous cell carcinoma model. For the tumour cure experiments, single dose irradiations were given following different regimens of polarographic pO₂ measurements associated with different degrees of mechanical tissue damage. With a dose of 32 Gy, 57% of animals were cured. Following 3 tracks of needle measurements, 73% of tumours were locally controlled, and 75% were cured after 8 needle tracks. The polarographic measurements gave virtually identical oxygenation data for recurrent or cured tumours (both median pO₂ 1.0 mmHg), respectively. There was thus no evidence of decreased radiosensitivity associated with tissue damage after invasive pO₂ measurements. The pre-therapeutic oxygenation status gave no evidence for a prediction of radiation response on an individual basis. (orig.)

[en] The authors report on a series of 37 biopsies from human soft-tissue sarcomas that were established in monolayer culture and tested for spheroid growth in early passage. The radiosensitivity, capacity of sublethal damage repair and number of spheroid rescuing units (SRU) were determined operationally from dose-cure curves of spheroids after fractionated irradiation. This was done by a direct fit of the α/β model to the quantal response data assuming Poisson cure statistics (Thames et al. 1986), in order to look for scatter of these parameters in this clinically radioresistant tumour type. (author)

No abstract available

[en] Published in summary form only