In-vitro-Untersuchungen zur PDR-Brachytherapie

Background

Calculations on the basis on the LQ-model have been focussed on the possible radiobiological equivalence between common continuous low dose rate irradiation (CLDR) and a superfractionated irradiation (PDR=pulsed dose rate) provided that the same total dose will be prescribed in the same overall time as with the low doserate. A clinically usable fractionation scheme for brachytherapy was recommended by Brenner and Hall and should replace the classical CLDR brachytherapy with line sources with an afterloading technique using a stepping source. The hypothesis that LDR equivalency can be achieved by superfractionation was tested by means of in vitro experiments on V79 cells in monolayer and spheroid cultures as well as on HeLa monolayers.

Materials and Methods

Simulating the clinical situation in PDR brachytherapy, fractionation experiments were carried out in the dose rate gradient of afterloading sources. Different dose levels were produced with the same number of fractions in the same overall incubation time. The fractionation schedules which were to be compared with a CLDR reference curve were: 40×0.47 Gy, 20×0.94 Gy, 10×1.88 Gy, 5×3.76 Gy, 2×9.4 Gy given in a period of 20 h and 1×18.8 Gy as a “single dose” exposition. As measured by flow cytometry, the influence of the dose rate in the pulse on cell survival and on cell cycle distribution under superfractionation was examined on V79 cells.

Results

V79 spheroids as a model for a slowly growing tumor, reacted according to the radiobiological calculations, as a CLDR equivalency was achieved with increasing fractionation. Rapidly growing V79 monolayer cells showed an inverse fractionation effect. A superfractionated irradiation with pulses of 0.94 Gy/h respectively 0.47 Gy/0.5 h was significantly more effective than the CLDR irradiation. This inverse fractionation effect in log-phase V79 cells could be attributed to the accumulation of cycling cells in the radiosensitive G2/M phase (G2 block) during protected exposure which was drastically more pronounced for the pulsed scheme. HeLa cells were rather insensitive to changes of fractionation. Superfractionation as well as hypofractionation yielded CLDR equivalent survival curves.

Conclusions

The fractionation scheme, derived from the PDR theory to achieve CLDR equivalent effects, is valid for many cell lines, however not for all. Proliferation and dose rate dependend cell cycle effects modify predictions derived from the sublethal damage recovery model and can influence acute irradiation effects significantly. Dose rate sensitivity and rapid proliferation favour cell cycle effects and substantiate, applied to the clinical situation, the possibility of a higher effectiveness of the pulsed irradiation on rapidly growing tumors.     

Changes in RBE of 14-MeV (d+T) neutrons for V79 cells irradiated in air and in a phantom: Is RBE enhanced near the surface?

Purpose

The relative biological effectiveness (RBE) for inacivation of V79 cells was determined as function of dose at the Heidelberg 14-MeV (d+T) neutron therapy facility after irradiation with single doses in air and at different depths in a therapy phantom. Furthermore, to assess the reproducibility of RBE determinations in different experiments we examined the relationship between the interexperimental variation in radiosensitivity towards neutrons with that towards low LET⁶⁰Co photons.

Methods

Clonogenic survival of V79 cells was determined using the colony formation assay. The cells were irradiated in suspension in small volumes (1.2 ml) free in air or at defined positions in the perspex phantom. Neutron doses were in the range, D₁=0.5–4 Gy.⁶⁰Co photons were used as reference radiation.

Results

The radiosensitivity towards neutrons varied considerably less between individual experiments than that towards photons and also less than RBE. However, the mean sensitivity of different series was relatively constant. RBE increased with decreasing dose per fraction from RBE=2.3 at 4 Gy to RBE=3.1 at 0.5 Gy. No significant difference in RBE could be detected between irradiation at 1.6 cm and 9.4 cm depth in the phantom. However, an approximately 20% higher RBE was found for irradiation free in air compared with inside the phantom. Combining the two effects, irradiation with 0.5 Gy free in air yielded an approximately 40% higher RBE than a dose of 2 Gy inside the phantom

Conclusion

The measured values of RBE as function of dose per fraction within the phantom is consistent with the energy of the neutron beam. The increased RBE free in air, however, is greater than expected from microdosimetric parameters of the beam and may be due to slow recoil protons produced by interaction of multiply scattered neutrons or to an increased contribution of α particles from C(n,α) reactions near the surface. An enhanced RBE in subcutaneous layers of skin combined with an increase in RBE at low doses per fraction outside the target volume could potentially have significant consequences for normal tissue reactions in radiotherapy patients treated with fast neutrons.     

Prospektive Studie zur Vermeidung heterotoper Ossifikationen nach Hüftgelenksersatz

Purpose

Two prospective trials were undertaken to assess the comparative efficacy of early postoperative irradiation with different radiation doses versus the postoperative use of nonsteroidal antiinflammatory drugs (NSAID) for prevention of heterotopic ossification (HO) following prothetic total hip replacement (THP).

Patients and Method

Between 1992 and 1994 585 patients received THP. These patients were randomwed in two longitudinal studies each with 3 treatment arms comparing postoperative irradiation with 4×3 Gy (101 patients), 1×5 Gy (93 patients), 1×7 Gy (95 patients) and the postoperative use of the NSAID indometacin for 7 days (113 patients) respectively for 14 days (90 patients) und acetyl salicyl acid (ASS) for 14 days (93 patients). Heterotopic ossification was scored according to the Brooker grading system. One hundred patients receiving no prophylactic therapy after total hip arthroplasty between 1988 and 1992 were analysed and defined as historical control group.

Results

Incidence of heterotopic ossification was 5% in the 4×3 Gy group (Brooker grade I 5%, grade II 0%, grade III 0%), 30,5% in the 1×5 Gy group (Brooker grade I 24,7%, grade II 4,1%, grade III 1.0%) and 10,5% in the 1×7 Gy group (Brooker grade I 10.5%, grade II 0%, grade III 0%). 15.9% of the indometacin-7 days-group developed heterotopic ossification (Brooker grade I 8%, grade II 6.2%, grade III 1.7%, grade IV 0%), 12.2% of the indometacin-14 days-group (Brooker grade I 8.9%, grade II 2.2%, grade III 1.1%) and 37.5% of the ASS-group (Brooker grade I 27.9%, grade II 4.3%, grade III 5.3%). The lowest incidence of heterotopic ossification was found for the 4××3 Gy and the 1×7 Gy group, but no significant difference between these two different treatments was observed.

Conclusion

Prophylactic irradiation of the operative site after hip replacement is more effective than the use of NSAID. Because no significant difference between the fractionated ingle dose irradiation was found and the latter is more comfortable for patients and more economical, irradiation with single 7 Gy fraction should be prefered.     

Effekte von Fraktionierung und Dosisleistung bei der PDR-Brachytherapie von B14-Zellen

Purpose

Present radiobiological studies for different cell lines in vitro demonstrate the equivalence and efficacy of continuous low-dose-rate brachytherapy (LDR-BT) and pulsed dose rate brachytherapy (PDR-BT) when using small and frequent dose pulses. The aim of this study was to examine monolayer fibroblast cultures in vitro to examine the biological effects of different pulse doses and dose rates under clinically conditiones.

Material and Methods

B14 cells, Hy B14 FAF 28, peritoneal fibroblasts, were cultured in multi-well plates and exposed to a PDR radiation source at a distance of 9 mm. The following PDR-schemes were compared: dose per pulse: 1 Gy, 2.5 Gy and 5 Gy to a total dose of 5 Gy/5 h (overall time). 10 Gy/10 h, 20 Gy/20 h and 30 Gy/30 h. The pulse duration for the examination of dose rate effects was 20 min, 30 min or 52 min corresponding to a pulse dose rate of 300 cGy/h, 200 cGy/h or 115 cGy/h. Treatment endpoints were cell survival measured by dye exclusion test and clonogenic cell survival.

Results

Cell survival decreased for pulse doses of 5 Gy compared to 2.5 Gy or 1 Gy per pulse (mean dose rate 200 to 300 cGy/h). No differences were observed with dose rates during irradiation of 300 cGy/h, 200 cGy/h or 115 cGy/h (20 Gy/l Gy).

Conclusion

Radiobiological effects of PDR-BT are dependent on the dose per pulse, with differences in biological effects only with a dose per pulse of more than 2.5 Gy, considering the described in-vitro conditiones. More examinations with a more pronounced difference in dose rate will be continued for evaluation of dose rate effects.     

Radiation-induced changes in breathing frequency and lung histology of C57BL/6J mice are time- and dose-dependent

Purpose

Pneumonitis and fibrosis constitute serious adverse effects of radiotherapy in the thoracic region. In this study, time-course and dose-dependence of clinically relevant parameters of radiation-induced lung injury in C57BL/6J mice were analyzed. A well-characterized disease model is necessary for the analysis of the cellular and molecular mechanisms using genetically modified mice.

Material and methods

C57BL/6J mice received single dose right hemithorax irradiation with 12.5 or 22.5?Gy. Body weight and breathing frequency were recorded as parameters for health impairment. Lung tissue was collected over 24?weeks for histological analysis.

Results

Hemithorax irradiation with 12.5 or 22.5?Gy induced biphasic breathing impairment with the first increase between days 7 and 70. Although breathing impairment was more pronounced in the 22.5?Gy group, it was accompanied in both dose groups by pneumonitis-associated histological changes. A second rise in breathing frequency ratios became visible starting on day 70 with a steady increase until day 210. Again, breathing was more strongly affected in the 22.5?Gy group. However, breathing impairment coincided only in the 22.5?Gy group with a significant increase in collagen deposition in the lung tissue by day 210. Tissue inflammation and fibrosis were observed in the irradiated and the shielded lungs, pointing toward involvement of systemic effects.

Conclusion

Hemithorax irradiation induces time-dependent pneumonitis and fibrosis in C57BL/6J mice. While hemithorax irradiation with 12.5?Gy is sufficient to induce lung inflammation, it is below the threshold for collagen deposition and fibrosis development by day 210.     

Comparison of the Response of human FaDu squamous cell carcinoma in nude mice after hypofractionated-accelerated regimens and “curative” fractionation schedules

Background

It has been suggested that tumors respond differently after irradiation with 10 or more fractions than with less fractionated regimens and that extrapolation from experiments with only a few fractions to “curative” regimens may be invalid. To test this hypothesis, we compared hypofractionated-accelerated treatments with “curative” fractionation schedules in human squamous cell carcinoma in nude mice.

Material and Methods

FaDu tumors were transplanted subcutaneously into the hindleg of NMRI nu/nu mice. TCD₅₀ values, i. e., the dose necessary to control 50% of the tumors locally, were determined after irradiation under ambient blood flow conditions with 5 and 10 fractions in 5 days, 10 fractions in 10 days, and 30 fractions in 15 days, 6 weeks or 10 weeks.

Results

TCD₅₀ values of the hypofractionated regimens were not significantly different and varied from 41 to 46 Gy. The number of fractions given in the same overall time had no measurable effect on local tumor control. The TCD₅₀ after 30 fractions in 6 weeks was 30 Gy higher than after the hypofractionated regimens. This effect was caused by a substantial increase of TCD₅₀ with overall treatment time, the dose recovered per day was 0.82 Gy (95% CI 0.66; 0.96). {ie315-1} determined from all data was 58 Gy (13; infinite).

Conclusions

The results of the present study compare well with our previous findings after different “curative” fractionation schedules in the same tumor. Thus, our study does not support that tumors respond differently after application of 10 or more fractions compared to less fractionated regimens. The biological mechanisms that govern the radiation response of FaDu tumors appear to be the same for hypofractionated-accelerated and “curative” regimens. Since only one tumor was investigated, these results cannot be generalized at the present time.     

Time management in radiation oncology: development and evaluation of a modular system based on the example of rectal cancer treatment

Purpose

The goal was to develop and evaluate a modular system for measurement of the work times required by the various professional groups involved in radiation oncology before, during, and after serial radiation treatment (long-term irradiation with 25?C28 fractions of 1.8?Gy) based on the example of rectal cancer treatment.

Materials and methods

A panel of experts divided the work associated with providing radiation oncology treatment into modules (from the preparation of radiotherapy, RT planning and administration to the final examination and follow-up). The time required for completion of each module was measured by independent observers at four centers (Rostock, Bamberg, Düsseldorf, and Offenbach, Germany).

Results

A total of 1,769 data sets were collected from 63?patients with 10?C489 data sets per module. Some modules (informed consent procedure, routine treatments, CT planning) exhibited little deviation between centers, whereas others (especially medical and physical irradiation planning) exhibited a wide range of variation (e.g., 1?h 49?min to 6?h 56?min for physical irradiation planning). The mean work time per patient was 12?h 11?min for technicians, 2?h 59?min for physicists, and 7?h 6?min for physicians.

Conclusion

The modular system of time measurement proved to be reliable and produced comparable data at the different centers. Therefore, the German Society of Radiation Oncology (DEGRO) decided that it can be extended to other types of cancer (head and neck, prostate, and breast cancer) with appropriate modifications.     

Nachweis einer strahleninduzierten Produktion von Tumor-Nekrose-Faktor alpha im Ewing-Sarkom RM 82 in vitro und in vivo

Aim

The expression of cytokines plays an important role in the transmission of the effects of ionizing radiation to tumor cells and normal tissue. Tumor necrosis factor alpha (TNF α), a pleiotropic monokine, is of special interest because of its cytotoxic effect on tumor cells and the induction of hemorrhagic necrosis in tumors. We examined the influence of ionizing radiation on TNF α production in a human Ewing’s sarcoma cell line in vitro and in vivo.

Methods

The protein and mRNA levels of the Ewing’s sarcoma cell line RM 82 were examined in vitro with ?Enhanced Amplified Sensitivity Immunoassay” (EASIA) and semiquantitative RT-PCR before and after treatment with single doses of 2 to 40 Gy, 1 to 72 hours after irradiation. After successful transplantation to nude mice, the time and dose correlation of TNF α mRNA production was examined in vivo.

Results

In vitro, RM 82 had a basal protein level of TNF α of 20.1±4.3 pg/ml/10⁶ cells. We observed a time- and dose-dependent increase of TNF α expression with a maximum of 125 pg/ml/10⁶ (5.9fold) 24 hours after irradiation with 20 Gy. At the mRNA level, the maximal up-regulation occurred 6 to 12 hours after 10 Gy. In vivo, the xenograft tumor maintained the capacity of TNF α expression. Time-and dose-dependency in mRNA production showed a maximum increase 6 hours after treatment with 10 Gy.

Conclusions

The presented experiments show in vitro a dose- and time-dependent up-regulation of TNF α in the Ewing’s sarcoma cell line RM 82 on protein and mRNA level. For the first time this phenomenon was also observed in vivo in a human xenograft tumor. This tumor model could be used for further experiments to examine the role of TNF α as a biologic radiation response modifier in human tumors.     

The sensitivity of the in vitro cytokinesis-blocked micronucleus assay in lymphocytes for different and combined radiation qualities

Purpose

The dose-response relationship and the relative biological effectiveness (RBE) for the induction of micronuclei in lymphocytes was analyzed after irradiation in vitro with a 6-MeV neutron beam that was followed by 240-kV X-rays. The dose range of the combined exposure comprised 1 to 3 Gy. For reference, the dose-effect relationships found after X-ray (0.5 to 5 Gy)-and neutron (0.5 to 4 Gy) exposure applied separately are presented. The possibility of an interaction between the 2 radiation qualities is investigated by the method of isobole calculation termed “envelope of additivity”.

Methods

Micronuclei were analyzed in PHA-stimulated, cytokinesis-blocked human lymphocytes.

Results

The dose-response relationships for the micronucleus frequencies induced by the neutron irradiation, as well as by the mixed exposure, were linear. A saturation effect was indicated after neutron doses higher than 3 Gy. After low LET exposure the dose-response curves were describable by a linear-quadratic model. For neutron-induced micronucleus frequencies, RBE-values of 2 to 3 and for the combined exposure RBE values of 1.5 to 2 were calculated for a range of effect of 0.5 to 1.5 micronuclei/binucleated lymphocyte. No indication was found for an interaction between the damage induced by X-rays and that produced by neutrons under our experimental conditions.

Conclusions

These studies demonstrate a clear dependence of micronucleus induction on radiation quality and empha-size the usefulness of the micronucleus assay in biological dosimetry, also in cases in which high LET radiation or a mixed beam is involved as the radiation source.     

Induction chemotherapy followed by simultaneous hyperfractionated radiochemotherapy in advanced head and neck cancer

Purpose

To evaluate the feasibility of induction chemotherapy followed by concomitant chemotherapy and hyperfractionated irradiation in locally advanced, inoperable head and neck cancer.

Methods

A pilot study was undertaken comprising 3 cycles of cisplatinum (100 mg/m², day 1) and 5-fluorouracil (1000 mg/m² in continuous intravenous infusion over the first 120 h) followed by bifractionated radiotherapy applied to tumor/involved lymph nodes up to the dose of 74.4 Gy given in 2 fractions of 1.2 Gy daily for 5 days a week combined with concomitant weekly cisplatinum infusion (50 mg/m²).

Results

Six patients were enrolled in the study. All of them completed the protocol therapy. Severe mucositis and myelotoxicity were the most common acute side effects observed in all and in 5 of the patients, respectively. Acute toxicity required interruption of concomitant chemotherapy in 5 cases and in 2 interruption of radiotherapy was necessary. Opioid analgesic parenteral therapy was administered in 4 patients. Three of them had to be hospitalized. One patient experienced cerebral stroke 1 day after the completion of therapy and died 7 days later. Due to high acute toxicity, patient accrual was terminated after 6 patients. At the mean follow-up of 17 months, 4 patients are alive, 3 of them are free of disease and in 1 local progression has been diagnosed.

Conclusions

High acute toxicity of induction cisplatinum and 5-fluorouracil followed by concomitant cisplatinum and hyperfractionated irradiation calls for less toxic treatment schedules in locally advanced inoperable head and neck cancer.     

Sodium butyrate enemas in the treatment of acute radiation-induced proctitis in patients with prostate cancer and the impact on late proctitis

Purpose

To evaluate prospectively the effect of sodium butyrate enemas on the treatment of acute and the potential influence on late radiation-induced proctitis.

Patients and Methods

31 patients had been treated with sodium butyrate enemas for radiation-induced acute grade II proctitis which had developed after 40 Gy in median. During irradiation the toxicity was evaluated weekly by the Common Toxicity Criteria (CTC) and subsequently yearly by the RTOG (Radiation Therapy Oncology Group) and LENT-SOMA scale.

Results

23 of 31 patients (74%) experienced a decrease of CTC grade within 8 days on median. A statistical significant difference between the incidence and the severity of proctitis before start of treatment with sodium butyrate enemas compared to 14 days later and compared to the end of irradiation treatment course, respectively, was found. The median follow-up was 50 months. Twenty patients were recorded as suffering from no late proctitis symptom. Eleven patients suffered from grade I and 2 of these patients from grade II toxicity, too. No correlation was seen between the efficacy of butyrate enemas on acute proctitis and prevention or development of late toxicity, respectively.

Conclusion

Sodium butyrate enemas are effective in the treatment of acute radiation-induced proctitis in patients with prostate cancer but have no impact on the incidence and severity of late proctitis.     

Telethermographische Untersuchungen zur Wirkung von Immunglobulinen (Beriglobin®) auf das Wärmeabstrahlungsverhalten bei der Strahlendermatitis

Background

Immunoglobulines are supposed to have a soothing effect on the degree of dermatitides and mucositides caused by irradiation. Research so far has been based on empiric information or reports of case studies mostly basing on subjective criteria. This study reports on objective thermographic measuring of heat radiation of dermatitides developing in the course of radiotherapy in case of female patients receiving postoperative radiotherapy after breast preserving operation on mamma carcinoma. Idea behind this is that immunglobulines affect inflammations of skin induced by irradiation, then also one of theses parameters, in this case heat, would be subject to change.

Patients and Method

Sixteen patients received 10 ml Beriglobin^® before first and 5 ml after 5th and 10th radiation (corresponds to 0 Gy, 10 Gy and 20 Gy) as intragluteal injection. Before starting with radiation as well as after 10 Gy respectively applied, upper bodies of patients were examined thermographically until final dose of 50 Gy was reached. Here temperature progress on upper body halves exposed to irradiation was compared with the untreated halves as well as with upper bodies of control group consisting of 20 patients who had received no immunoglobuline injections.

Results

Patients who received immunoglobuline injections showed no differences in their skin temperature progress in comparison with the control group (Table 1, Figure 1). Skin temperature at the beginning as well as temperature progress during treatment and temperature at the end of treatment were identical in both groups. Also the relative temperature increase (temperature of body half subject to irradiation minus temperature of the other body half) was identical in both therapy groups (Table 2, Figure 2).

Conclusion

Immunoglobulines (Beriglobin^®) do not influence the course of thermal radiation due to dermatitis developing during a series of irradiation treatments. This results in the conclusion, that immunoglobulines do not have any influence in the vasodilatative part of dermatitis and vasodilatative redness respectively.     

The effect of paclitaxel on the radiosensitivity of gynecological tumor cells

Background

Paclitaxel, a natural product from Taxus brevifolia, is a microtubule stabilizing agent, which has been shown to block different cells in the G2/M phase of the cell cycle and consequently, to modulate their radioresponsiveness. Our aim was to test the cytotoxic and radiosensitizing potential of paclitaxel, with respect to different gynecological tumors with varying radiosensitivities.

Material and Method

We performed clonogenic assays and flow cytometry on 2 cell lines, MCF-7 (breast) and CaSki (cervix) cells, and on 2 primary ovarian tumor samples (OC-I and OC-II). The cells were irradiated with 200 kV X-rays, radiation doses of up to 8 Gy were applied either as single doses or in 2 Gy fractions. Paclitaxel concentrations varied from 0.07 to 700 nM, incubation times varied from 3 to 120 h.

Results

Paclitaxel alone changed the cell cycle distribution of the cells tested and was cytotoxic in a time and concentration dependent manner. When combined with radiation, most schedules resulted in additive effects of the combined treatments. However, for MCF-7 cells, when 7 nM paclitaxel, applied 24 h before irradiation, were combined with fractionated irradiation a supra-additive effect with a SER of 1.2 was found. For CaSki cells, under comparable conditions the SER was 1.13 but the effects were not statistically significant.

Conclusion

Under specific conditions, paclitaxel exerted a weak radiosensitizing effect on breast and cervical carcinoma cells. A therapeutic gain may be possible on the basis of an optimal paclitaxel/radiation scheduling.     

Effekte einer niedrig dosierten Co-60-Bestrahlung auf den Verlauf einer aseptischen Arthritis am Kniegelenk des Kaninchens

Purpose

Numerous clinical observations demonstrate the efficacy of low radiation doses in the treatment of painful osteoarthritis. Experimental investigations remain scarce. We investigated the effects of locally daily 5 times 1.0 Gy 60-Co irradiation on an artificially induced aseptic gonarthritis in rabbits.

Material and Methods

Three separate experiments (EV) were performed (10 rabbits per experiment, 5 treated/5 controls; duration: EV1: 18 days; EV2: 6 days; EV3: 29 days). An aseptic arthritis in the right knee joint of rabbits was induced by intraarticular injection of 0.5 ml papain solution (3%, 30,000 USP/mg) on day 0. The arthritic knee joint of the anesthesized animals was irradiated daily from day 1 to 5 with 5 times 1.0 Gy. The controls were sham-irradiated under the same conditions. The time course of arthritis in treated animals and sham-treated controls was evaluated by clinical laboratory-chemical and histological criteria. The clinical investigation was performed daily, the puncture of the kneejoints was carried out several times in EV1, and at the end of experiments in EV2 and EV3. At the end of the observation period, animals were killed and the knee joints excised for histological analysis.

Results

The intraarticular injection of papain caused a peracute inflammatory response in all animals. After 1 week the chronical stage was reached, and the experimental arthritis resolved slowly within several weeks. Local irradiation accelerated the decrease of inflammatory joint swelling, being significant by day 4. On day 6 the volume of synovial fluid in irradiated knee-joints was significantly smaller. The morphometric data indicated a reduction in thickness of synovial membrane, a decrease in number of synovial cell layers, and a decrease in distance between capillaries and the synovial membrane surface following irradiation of arthritic joints. Due to considerable individual variability, the morphometric data partially did not reach statistically significance.

Conclusion

The experiments provide evidence for an antiphlogistic effect of irradiation with 5 times 1.0 Gy in vivo. They support the clinical observations of the efficacy of anti-inflammatory radiotherapy.     

Attenuation of radiation-induced gastrointestinal damage by epidermal growth factor and bone marrow transplantation in mice

Purpose: We examined the effect of epidermal growth factor (EGF) and bone marrow transplantation (BMT) on gastrointestinal damage after high-dose irradiation of mice.

Material and methods: C57Black/6 mice were used. Two survival experiments were performed (12 and 13 Gy; ⁶⁰Co, 0.59–0.57 Gy/min). To evaluate BMT and EGF action, five groups were established – 0 Gy, 13 Gy, 13 Gy + EGF (at 2 mg/kg, first dose 24 h after irradiation and then every 48 h), 13 Gy + BMT (5 × 10⁶ cells from green fluorescent protein [GFP] syngenic mice, 4 h after irradiation), and 13 Gy + BMT + EGF. Survival data, blood cell counts, gastrointestine and liver parameters and GFP positive cell migration were measured.

Results: BMT and EGF (three doses, at 2 mg/kg, administered 1, 3 and 5 days after irradiation) significantly increased survival (13 Gy). In blood, progressive cytopenia was observed with BMT, EGF or their combination having no improving effect early after irradiation. In gastrointestinal system, BMT, EGF and their combination attenuated radiation-induced atrophy and increased regeneration during first week after irradiation with the combination being most effective. Signs of systemic inflammatory reaction were observed 30 days after irradiation.

Conclusions: Our data indicate that BMT together with EGF is a promising strategy in the treatment of high-dose whole-body irradiation damage.     

Chest wall radiotherapy with volumetric modulated arcs and the potential role of flattening filter free photon beams

Purpose

The goal of the work was to assess the role of RapidArc treatments in chest wall irradiation after mastectomy and determine the potential benefit of flattening filter free beams.

Methods and material

Planning CT scans of 10?women requiring post-mastectomy chest wall radiotherapy were included in the study. A dose of 50?Gy in 2?Gy fractions was prescribed. Organs at risk (OARs) delineated were heart, lungs, contralateral breast, and spinal cord. Dose–volume metrics were defined to quantify the quality of concurrent treatment plans assessing target coverage and sparing of OARs. Plans were designed for conformal 3D therapy (3DCRT) or for RapidArc with double partial arcs (RA). RapidArc plans were optimized for both conventional beams as well as for unflattened beams (RAF). The goal for this planning effort was to cover 100% of the planning target volume (PTV) with ≥?90% of the prescribed dose and to minimize the volume inside the PTV receiving >?105% of the dose. The mean ipsilateral lung dose was required to be lower than 15?Gy and V_20?Gy?Results All techniques met planning objectives for PTV and for lung (3DCRT marginally failed for V_20?Gy). RA plans showed superiority compared to 3DCRT in the medium to high dose region for the ipsilateral lung. Heart irradiation was minimized by RAF plans with ~4.5?Gy and ~15?Gy reduction in maximum dose compared to RA and 3DCRT, respectively. RAF resulted in superior plans compared to RA with respect to contralateral breast and lung with a reduction of ~1.7?Gy and 1.0?Gy in the respective mean doses.

Conclusion

RapidArc treatment resulted in acceptable plan quality with superior ipsilateral tissue sparing compared to traditional techniques. Flattening filter free beams, recently made available for clinical use, might provide further healthy tissue sparing, particularly in contralateral organs, suggesting their applicability for large and complex targets.     

Stellenwert der Radiochirurgie in der Primärtherapie des Glioblastoma multiforme

Aim

To describe the clinical results and the feasibility of a phase II dose escalation study of small boost target volumes with a radiosurgical technique in patients with positive early postoperative MRI scan.

Patients and Method

Since 1986, 35 patients were treated within a concept for first line therapy. Including criteria were residual tumor ≤5 cm and Karnofsky performance score ≥70. The mean age was 54.5 years. The treatment concept included an operation for reduction of tumor volume and a postoperative irradiation. The postoperative irradiation was divided in 2 parts: first, a hyperfractionated (1.8 Gy single dose twice a day, 54 Gy total dose) irradiation was performed containing the tumor and the edema with a 2 cm safety margin. Secondly, a radiosurgical boost dose was delivered. The target volume of this radiosurgery was the contrast enhancing residual tumor in early postoperative MRI scans. The median boost dose was 15 Gy. Survival curves were calculated according to the Kaplan-Meier method. Quality of life was evaluated using objective criteria such as neurological findings, frequency of seizures and steroid medication

Results

The median survival calculated from the time of diagnosis was 10.1 months. The 1- and 2-year survival rate were 35% and 6%, respectively. Young age tended to longer survival, patients younger than 53 years had a median survival of 10.4 months whereas patients older than 53 years showed a median survival of 9.2 months. The mean value of the boost volume was 22 cm³. Patients with smaller volumes had a median survival of 10.1 months and patients with bigger volumes showed a median survival of 9.9 months. 4.5 months after therapy, 75% of the patients showed improved or stable quality of life.

Conclusion

The feasibility of a radiosurgically delivered boost dose after postoperative irradiation could be demonstrated. The observed survival rate is comparable to the survival rates reported in the literature. Whether or not the radiosur gery after postoperative irradiation is able to prolong survival can only be evaluated in a randomized phase III trial.     

Recovery from sublethal damage and potentially lethal damage

Purpose

In order to clarify the biological response of tumor cells to proton beam irradiation, sublethal damage recovery (SLDR) and potentially lethal damage recovery (PLDR) induced after proton beam irradiation at the center of a 10?cm spread-out Bragg peak (SOBP) were compared with those seen after X?ray irradiation.

Methods

Cell survival was determined by a colony assay using EMT6 and human salivary gland tumor (HSG) cells. First, two doses of 4?Gy/GyE (Gray equivalents, GyE) were given at an interfraction interval of 0–6?h. Second, five fractions of 1.6?Gy/GyE were administered at interfraction intervals of 0–5?min. Third, a delayed-plating assay involving cells in plateau-phase cultures was conducted. The cells were plated in plastic dishes immediately or 2–24?h after being irradiated with 8?Gy/GyE of X?rays or proton beams. Furthermore, we investigated the degree of protection from the effects of X?rays or proton beams afforded by the radical scavenger dimethyl sulfoxide to estimate the contribution of the indirect effect of radiation.

Results

In both the first and second experiments, SLDR was more suppressed after proton beam irradiation than after X?ray irradiation. In the third experiment, there was no difference in PLDR between the proton beam and X?ray irradiation conditions. The degree of protection tended to be higher after X?ray irradiation than after proton beam irradiation.

Conclusion

Compared with that seen after X?ray irradiation, SLDR might take place to a lesser extent after proton beam irradiation at the center of a 10?cm SOBP, while the extent of PLDR does not differ significantly between these two conditions.

     

Possible Importance of PLD Repair in the Modulation of BrdUrd and IdUrd-mediated Radiosensitization in Plateau-phase C3H10T1/2 Mouse Embryo Cells

Summary

C3H10T1/2 mouse embryo cells exhibiting strong contact inhibition of growth at confluency were grown in the presence of 5-bromodeoxyuridine (BrdUrd) or 5-iododeoxyuridine (IdUrd) (0–1·2 μm) with daily refeeding and exposed to γ-rays (6 Gy) either in the logarithmic or the plateau phase of growth. Sensitization to radiation was observed in both growth states with increasing concentration of BrdUrd or IdUrd but the degree of sensitization achieved was lower for plateau-phase cells. Because the degree of [H³]BrdUrd incorporation was found to be similar in exponentially growing and plateau-phase cells, it is hypothesized that the radiosensitization caused by pyrimidine analogues may be affected by the physiological state of the cells at the time of irradiation. Delayed plating of pleateau-phase cells (6 h) caused an increase in survival, indicating repair of potentially lethal damage (PLD). A greater increase in cell survival was observed in cells that had been grown in the presence of BrdUrd and IdUrd and it was found to increase with increasing concentrations. This analogue-concentration dependent PLD repair activity resulted in an almost complete loss of the radiosensitizing effect in delayed plated plateau-phase cells up to a concentration of about 0·6 μM of BrdUrd and IdUrd. Both compounds, but especially BrdUrd, caused a relaxation in the mechanism of contact inhibition and led to higher cell densities in the plateau phase. The results suggest that repair and/or expression of PLD might be involved in the mechanism underlying BrdUrd and IdUrd-mediated radiosensitization and point out the potential importance of PLD repair in the modulation of the radiosensitizing effect of these compounds in their clinical application.