Image-based lung functional radiotherapy planning for non-small cell lung cancer.

BACKGROUND: This simulation study assessed the feasibility and impact of incorporating additional information from lung perfusion single-photon emission computed tomography (SPECT) into intensity-modulated radiotherapy planning for the treatment of non-small cell lung cancer (NSCLC). METHODS: In this simulation study, data of 13 patients with stage I-III NSCLC previously treated by radio(chemo)therapy were used. The SPECT was fused together with radiotherapy planning CT. Functional lung regions (FL) and non-functional lung regions (nFL) were defined based on SPECT images. Four treatment plans were created for each patient: an IMRT and a VMAT plan with planning CT (anatomical plans), and an IMRT and a VMATplan which integrate the additional information from lung perfusion scintigraphy (function plans). Dosimetric parameters were compared between all plans for PTV parameters and normal tissue preservation, focusing on optimizing the lung volume receiving at least 20 Gy (V20Gy). RESULTS: Compared to anatomical plans, functional IMRT and functional VMAT plans reduced functional lung V20Gy in all cases of local and diffuse hypoperfusion patterns of SPECT defects. Similar results were observed for functional lung V30Gy and median dose to functional lung Dmean, but were not statistically significant in any group. A significant increase in non-functional lung V20Gy resulted in both functional plans. There were no significant differences in conformity or heterogeneity indices or PTV median doses between either pair of anatomical and functional plans. CONCLUSION: The incorporation of functional imaging for radiotherapy planning in non-small cell lung cancer is feasible and appears to be beneficial in preserving a functional lung in non-small cell lung cancer.

Treatment approaches to primary tracheal cancer.

A patient identified with tracheal cancer benefits most from evaluation by an experienced center and an extensive effort to assess the possibility of a complete surgical resection as the most efficient treatment option for cure. Localized, nonoperable disease may still be controlled by combined modality using chemotherapy and concurrent radiation.

Evaluation of different biomarkers to predict individual radiosensitivity in an inter-laboratory comparison--lessons for future studies.

Radiotherapy is a powerful cure for several types of solid tumours, but its application is often limited because of severe side effects in individual patients. With the aim to find biomarkers capable of predicting normal tissue side reactions we analysed the radiation responses of cells from individual head and neck tumour and breast cancer patients of different clinical radiosensitivity in a multicentric study. Multiple parameters of cellular radiosensitivity were analysed in coded samples of peripheral blood lymphocytes (PBLs) and derived lymphoblastoid cell lines (LCLs) from 15 clinical radio-hypersensitive tumour patients and compared to age- and sex-matched non-radiosensitive patient controls and 15 lymphoblastoid cell lines from age- and sex- matched healthy controls of the KORA study. Experimental parameters included ionizing radiation (IR)-induced cell death (AnnexinV), induction and repair of DNA strand breaks (Comet assay), induction of yH2AX foci (as a result of DNA double strand breaks), and whole genome expression analyses. Considerable inter-individual differences in IR-induced DNA strand breaks and their repair and/or cell death could be detected in primary and immortalised cells with the applied assays. The group of clinically radiosensitive patients was not unequivocally distinguishable from normal responding patients nor were individual overreacting patients in the test system unambiguously identified by two different laboratories. Thus, the in vitro test systems investigated here seem not to be appropriate for a general prediction of clinical reactions during or after radiotherapy due to the experimental variability compared to the small effect of radiation sensitivity. Genome-wide expression analysis however revealed a set of 67 marker genes which were differentially induced 6 h after in vitro-irradiation in lymphocytes from radio-hypersensitive and non-radiosensitive patients. These results warrant future validation in larger cohorts in order to determine parameters potentially predictive for clinical radiosensitivity.

Heterogeneity of radiation- and TNF-alpha-induced programmed cell death in carcinoma, sarcoma and lymphoma cell lines.

AIM: To characterize the interaction of tumour necrosis factor alpha (TNF-alpha) and ionising radiation in six sarcoma, lymphoma and carcinoma cell lines. MATERIALS AND METHODS: Cells were characterized regarding annexin V/propiduim iodine affinity and caspase-3 status after application of TNF-alpha, radiation, or combined treatment. RESULTS: Three cell lines showed similar results with additive effects of TNF-alpha and radiation in both assays. The other three cell lines significantly differed regarding the detection of apoptotic cells between treatment conditions (radiation and/or TNF application) and between the two apoptosis assays. CONCLUSION: The interaction between TNF-alpha and radiation differs between tumour entities and cannot be described by using only one parameter.

Kidney-autotransplantation before radiotherapy: a case report.

BACKGROUND: A 28-year-old man suffering from a Ewing tumour arising from the 9th-11th ribs with infiltration of neuroforamina without distant metastases was planned to receive radiotherapy following primary intralesional surgery and induction chemotherapy. Due to pleural infiltration and effusion, a hemithorax irradiation with a sequential boost to the primary tumour site had to be administered. Different treatment planning variants failed to provide sufficient radiotherapy planning in view of target volume coverage and avoidance of organs at risk, especially due to high calculated radiation doses potentially compromising the left kidney. MATERIALS AND METHODS: To prevent left kidney organ exposure, an autotransplantation of the left kidney into the right fossa iliaca was performed. An infiltration of the kidney was initially excluded. RESULTS: Postoperatively, a renal scintigraphy showed a normal function of both kidneys allowing sufficient radiotherapy treatment planning. Target volume coverage was easily obtained using a combination of hemithorax irradiation and a sequential boost by an intensity-modulated-radiotherapy technique. CONCLUSION: In difficult individual treatment situations, surgical transpositions as well as organ autotransplantation might be useful in reducing radiotherapy organ dose levels.

Impact of (18)F-FDG-PET/CT on staging and irradiation of patients with locally advanced rectal cancer.

PURPOSE: To investigate the impact of fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) on planning of neoadjuvant radiotherapy for locally advanced rectal cancer (LARC) patients. PATIENTS AND METHODS: From January 2003 to December 2007, a total of 36 patients with LARC underwent a retroprospective PET/CT study for radiotherapy-planning purposes. Gross tumor volume (GTV), clinical target volume (CTV) and planning target volume (PTV) were defined in a retrospective analysis by a blinded reader. The hypothetical boost volume was defined primarily on CT alone, and afterwards on the fused PET/CT dataset. The CT- and PET/CT-based GTVs were quantitatively compared and percentage of overlap (OV%) was calculated and analyzed. The impact of PET/CT on radiation treatment planning and overall patient management was evaluated. RESULTS: PET/CT-GTVs were smaller than CT-GTVs (p < 0.05). PET/CT imaging resulted in a change of overall management for three patients (8 %). In 16 of 35 patients (46 %), PET/CT resulted in a need for modification of the usual target volumes (CT-PTV) because of detection of a geographic miss. CONCLUSION: FDG-PET/CT had significant impact on radiotherapy planning and overall treatment of patients with LARC.

Multicentric investigation of ionising radiation-induced cell death as a predictive parameter of individual radiosensitivity.

In the present study, the predictive value of ionising radiation (IR)-induced cell death was tested in peripheral blood lymphocytes (PBLs) and their corresponding Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) in an interlaboratory comparison. PBLs and their corresponding LCLs were derived from 15 tumour patients, that were considered clinically radiosensitive based on acute side-effects, and matched controls. Upon coding of the samples, radiosensitivity of the matched pairs was analysed in parallel in three different laboratories by assessing radiation-induced apoptotic and necrotic cell death using annexin V. All participating laboratories detected a dose-dependent increase of apoptosis and necrosis in the individual samples, to a very similar extent. However, comparing the mean values of apoptotic and necrotic levels derived from PBLs of the radiosensitive cohort with the mean values of the control cohort did not reveal a significant difference. Furthermore, within 15 matched pairs, no sample was unambiguously and independently identified by all three participating laboratories to demonstrate in vitro hypersensitivity that matched the clinical hypersensitivity. As has been reported previously, apoptotic and necrotic cell death is barely detectable in immortalised LCL derivatives using low doses of IR. Concomitantly, the differences in apoptosis or necrosis levels found in primary cells of different individuals were not observed in the corresponding LCL derivatives. All participating laboratories concordantly reasoned that, with the methods applied here, IR-induced cell death in PBLs is unsuitable to unequivocally predict the individual clinical radiosensitivity of cancer patients. Furthermore, LCLs do not reflect the physiological properties of the corresponding primary blood lymphocytes with regard to IR-induced cell death. Their value to predict clinical radiosensitivity is thus highly questionable.

Late effects of thoracic irradiation in children.

PURPOSE: To summarize the literature regarding the late effects of radiotherapy to the thorax in childhood and adolescence with special emphasis on cardiac and pulmonary impairment. MATERIAL AND METHODS: The literature was critically reviewed using the PubMed database with the key words "late effects", "late sequelae", "child", "childhood", "adolescence", "radiation", "radiotherapy", "thorax", "lung", "heart", and "pulmonary". RESULTS: 17 publications dealing with radiation-induced pulmonary and cardiac late sequelae in children could be identified and were analyzed in detail. 29 further publications with additional information were also included in the analysis. Pulmonary function impairment after mediastinal irradiation arose in one third of all pediatric patients, even when treatment was performed with normofractionated lower doses (15-25 Gy). Whole lung irradiation was regularly followed by pulmonary function impairment with differing rates in several reports. However, clinically symptomatic function impairment like dyspnea was less frequent. Irradiation of up to 25 Gy (single doses < or = 2 Gy) to the heart showed little or no cardiac toxicity in analyses of irradiated children (median follow-up 1.3-14.3 years). Doses of > 25 Gy (single doses < or = 2-3.3 Gy) led to several cardiac dysfunctions. However, new data from adults with longer follow-up may indicate threshold doses as low as 1 Gy. Impairment of skeletal growth, breast hypoplasia, and secondary malignancy were further potential late sequelae. CONCLUSION: Several retrospective reports described radiation-associated late sequelae in children. However, there is still a lack of sufficient data regarding the characterization of dose-volume effects.

Whole lung irradiation in patients with exclusively pulmonary metastases of Ewing tumors. Toxicity analysis and treatment results of the EICESS-92 trial.

BACKGROUND: In the European Intergroup Cooperative Ewing's Sarcoma Study (EICESS) 92, whole lung irradiation (WLI) was performed in patients with primary lung metastases. This retrospective analysis evaluates the pulmonary function and the outcome of patients with exclusively pulmonary metastases. PATIENTS AND METHODS: Between 1990 and 1999, 99 patients were registered into the EICESS-92-study trial with exclusively pulmonary metastases of Ewing tumors. The multimodal treatment regimen included polychemotherapy and local therapy to the primary tumor. WLI was performed with a dose between 12-21 Gy. 70 patients were treated with WLI, 13 of them received a further boost to their primary tumor in the thorax up to a cumulative dose of 54 Gy. RESULTS: Pulmonary function tests were available for 37 patients treated with WLI (+/- boost). None, mild, moderate or severe pulmonary complications were seen in 43%, 29%, 21% and 7% of patients treated with WLI without further boost (median follow-up 25.2 months). Patients with an additional radiation boost or surgery to the thorax showed slightly higher rates of complications. Overall survival (OAS) showed a trend towards better results for patients with WLI (5-year-OAS: 0.61 for WLI vs. 0.49 for no WLI, p = 0.36). CONCLUSION: These data indicate a benefit and acceptable toxicity for WLI in the presented collective of patients. As long as there is no randomized prospective analysis, the present data confirm the indication for WLI in Ewing tumor patients with primary exclusively lung metastases.

Perioperative high-dose rate brachytherapy using a bendy applicator (flab): treatment results of 74 patients.

BACKGROUND: Radiotherapy plays a pivotal role in tumor treatment. Brachytherapy as an additional radiation technique allows local dose increments in areas at high risk of local failure. PATIENTS AND METHODS: Our past 15-year experience with tissue-equivalent bendy applicator brachytherapy at the University Hospital Münster, Germany was reviewed. A series of 74 consecutive patients who had mainly been treated for sarcomas with perioperative brachytherapy was analyzed with a focus on local relapse-free survival and side-effects. RESULTS: The 5-year local control rate was 73% in primary treatment situations with a significant influence of additional external irradiation, surgical margin depth and tumor entity. Late sequelae of combined modality treatment were observed in 40 patients (54%) and mainly concerned wound healing (n = 18, 24%). CONCLUSION: A high-risk collective, in view of local failure, showed adequate local control rates as well as acceptable late sequelae. Flab brachytherapy is a good treatment option to achieve local radiation dose increments in patients at high risk of local failure.

Rectum dose reduction and individual treatment plan optimization for high-dose-rate prostate brachytherapy.

PURPOSE: Different doses and techniques used in high-dose-rate (HDR) prostate brachytherapy make it difficult to define universal quality parameters. The aim of this study was to develop individual, objective parameters for the evaluation of an HDR brachytherapy plan for prostate radiation. METHODS: Fifty-three patients who received an HDR brachytherapy boost after external radiation were analyzed in this study. Brachytherapy was performed with a (192)Ir source after ultrasound-guided, transperineal metal needle application followed by removal of the ultrasound probe to reduce organ dose levels at the anterior rectum wall. The rectum and prostate locations as well as the dose at the anterior rectum wall were estimated under the anatomical conditions of HDR prostate brachytherapy. The doses at the organs at risk (rectum and urethra) were analyzed for several parameters, which were compared to values of former patients before the start of treatment. In cases of major deviations, modifications of the treatment plan were performed before starting the treatment. RESULTS: Deflating of the water balloon led to an increase of the space between the anterior rectal wall and the dorsal margin of the prostate (mean, 6mm; 1-10mm). The dose of the introduced "virtual rectum," represented by the ventral surface of the ultrasound probe, in the treatment plan correlated to dose measurements in the rectum. Pretreatment evaluation and comparison of the established individual quality parameters led in two cases to a treatment plan modification. CONCLUSIONS: This method allows a fast and objective individual brachytherapy treatment plan evaluation and improvement.

Organ movements and dose exposures in teletherapy of prostate cancer using a rectal balloon.

BACKGROUND AND PURPOSE: During radiotherapy of localized prostate cancer, organ movements for the dose exposure of organs at risk like rectum, urinary bladder and urethra play, inter alia, a significant role. One possibility of internal organ stabilizing is offered by the usage of a rectal balloon during radiotherapy. The influence on organ movements and dose allocation of the organs at risk is unknown. PATIENTS AND METHODS: Twelve patients (Table 1) were characterized based on planning-CT's regarding organ movements and organ doses using a rectal balloon, inflated with 0 ml and 60 ml air. For the determination of the organ doses, three-dimensional conformal radiation plans (3-field-pelvis box) with a cumulative dose of 59.4 Gy were created, and the dose-volume-histograms for the anterior rectal wall, the posterior rectal wall, the rectal mucosa, the whole rectum, as well as the urinary bladder were compared (Figures 1 and 2). RESULTS: The application of a 60 ml air-filled rectal balloon during each fraction of teletherapy led to significant organ movements of the anterior and posterior rectal wall and to a reduction of the transversal prostate diameter, as well as to a changed organ dose exposure of the organs at risk. A ventral shift of the anterior rectal wall (maximum 0.8 cm, mean 0.4 cm) was shown, as well as a dorsal shift of the posterior rectal wall (maximum 1.2 cm, mean 0.7 cm), associated with a transversal prostate diameter decrease (maximum 0.8 cm, mean 0.3 cm) (Table 2, Figure 3). The organ dose of the anterior rectal wall increased significantly (maximum 1.3 Gy, mean 0.5 Gy) during application of a rectal balloon, the one of the posterior rectal wall decreased significantly (maximum 18.6 Gy, mean 6.5 Gy). Related to the entire rectal mucosa and the rectum as a complete organ, a decrease of the maximum doses was shown (rectal mucosa: maximum 9.1 Gy, mean 3.0 Gy; rectum: maximum 9.4 Gy, mean 3.7 Gy). The organ dose of the urinary bladder did not show significant changes (Tables 3 and 4, Figures 4 to 7). CONCLUSION: The application of a rectal balloon in teletherapy of localized prostate cancer leads to significantly changed dose exposition of organs at risk. The decreased dose exposure of the posterior rectal wall and the rectal mucosa is opposed by the higher organ dose of the anterior rectal wall. It has to be shown weather documented organ dose exposure is associated with short and long-term consequences.

Ovarian function following pelvic irradiation in prepubertal and pubertal girls and young adult women.

PURPOSE: To analyze the effect of pelvic radiotherapy on ovarian function in prepubertal and pubertal girls and young adult women. PATIENTS AND METHODS: In a retrospective monoinstitutional analysis, patients < 30 years of age at diagnosis were included who had been irradiated between 1979 and 1998. The main tumor types were Hodgkin's disease (38%), Ewing's sarcoma (20%) and nephroblastoma (11%). Patients were classified into three groups according to the position of the ovary in relation to the radiation portals. Group 1 was defined by direct irradiation of both ovaries. Group 2 patients were included with both ovaries potentially located in the radiation portals. In group 3, at least one ovary was not directly irradiated. The median follow-up was 128 months. RESULTS: 16 of 55 analyzed patients were categorized in group 1. In ten of these patients, hormone status was evaluable. The ovarian doses were >/= 15 Gy. Except for one patient treated with 15 Gy all developed hormone failure. Eight of 14 patients of group 2 were evaluable. Seven of these patients developed ovarian failure. 19 of 24 patients in group 3 were evaluable. Nine of these patients developed ovarian failure. The observed difference in the rate of ovarian failure between the groups is statistically significant (p = 0.045). CONCLUSION: All patients receiving > 15 Gy to the ovaries developed hormone failure. In one case of a patient receiving an ovarian dose of 15 Gy, hormone failure was not found. In case of pelvic irradiation excluding at least one ovary, approximately half of the patients developed ovarian dysfunction, probably also due to the effects of polychemotherapy.

Radiotherapy of benign diseases-scleredema adultorum Buschke.

BACKGROUND: Scleredema adultorum Buschke is a rare disorder characterized by thickening of the dermis of the neck, head and upper trunk. Its etiology is unknown, but there may be a preceding history of infection and there is a known association with diabetes mellitus. Women are more frequently affected. Usually, the disease is self-limiting but some patients show progressive disease. In these cases therapeutic options are poor, with only case reports and small series supporting their use. CASE REPORT: A 58-year-old patient with a scleredema of the neck and upper trunk is described, who was treated twice within 6 months by electron-beam radiation therapy. After the second course his symptoms improved significantly. A review of the literature of radiation treatment of this disease is given. CONCLUSION: . Regardless of the possible mechanisms in pathogenesis and treatment of scleredema adultorum Buschke, the application of ionizing radiation is an important, effective and well-tolerated therapy option in the treatment of severe cases and may candidate as the first-line treatment of this disease.

Changed adhesion molecule profile of Ewing tumor cell lines and xenografts under the influence of ionizing radiation.

BACKGROUND: Adhesion molecules are involved in cell-cell and cell-matrix interactions and may be informative to characterize intercellular mechanisms of invasion and metastasis. This study was performed to characterize radiation-induced changes in the adhesion molecule profile of Ewing tumor subpopulations on a single cell level. MATERIALS AND METHODS: In the present study, two Ewing tumors were characterized in vitro 4, 24 and 72 hours after radiation with 5 Gy and in vivo in a xenograft model 4, 6 and 15 days after radiation with 30 Gy, together with non-irradiated controls, by five parameter flow cytometry. Directly fluorescence-conjugated antibodies that were directed against adhesion molecules (LFA-1 (CD11a), HCAM (CD44), VLA-2 (CD49b), ICAM-1 (CD54), NCAM (CD56), LECAM-1 (CD62L) and CD86) were used. Annexin V and 7-AAD were used to characterize radiation-induced apoptosis. RESULTS: Tumor cell subpopulations were identified by the expression of adhesion molecules, apoptotic markers and DNA content. Heterogeneous changes of the adhesion molecule profile were identified on tumor cell subpopulations after radiation. The expression of CD11a and CD62L correlated with the expression of apoptosis-associated markers. CONCLUSION: The changes of flow cytometric profile under radiation may potentially correlate with a changed metastatic potential of tumor cell subpopulations.

Early effects of irradiation on [(123)I]-IMT and [(18)F]-FDG uptake in rat C6 glioma cells.

BACKGROUND: Single-photon emission computed tomography (SPECT) using 3-[(123)I]-iodo-L-alpha-methyltyrosine ([(123)I]-IMT) and positron emission tomography (PET) using 2-[(18)F]-fluoro-2-deoxy-D-glucose ([(18)F]-FDG) are valuable tools for the distinction between viable tumor and radionecrosis in patients receiving radiotherapy for high-grade gliomas. However, to date, little is known about the early effects of radiation on [(123)I]-IMT and [(18)F]-FDG uptake in gliomas. MATERIAL AND METHODS: To determine the early effects of irradiation on [(123)I]-IMT and [(18)F]-FDG uptake in gliomas, in vitro studies were performed using rat C6 glioma cells. The glioma cells were irradiated with 20 Gy which is a common dose applied to patients receiving intraoperative radiotherapy. Subsequently, the early kinetics of [(123)I]-IMT and [(18)F]-FDG uptake in glioma cells were monitored for 3 days. RESULTS: Micromorphometric examinations of the irradiated glioma cells revealed that about 25% of the viable cells transformed into giant cells. [(123)I]-IMT uptake per 10(5) viable glioma cells was unchanged on the 1st day post irradiation, but showed a significant increase on the 2nd and 3rd day following radiotherapy (p < 0.01). In addition, there was a moderate increase in [(18)F]- FDG accumulation per 10(5) viable glioma cells during the first 3 days after irradiation (p < 0.05). The maximum increase in early [(123)I]-IMT uptake 1 h after application surpassed that of [(18)F]-FDG (p < 0.01). CONCLUSION: Rat C6 glioma cells show an early increase in [(123)I]-IMT and [(18)F]-FDG uptake following irradiation which may be partly due to giant cell formation. These data suggest that [(123)I]-IMT SPECT and [(18)F]-FDG PET may be promising procedures for the early prediction of the therapeutic response of gliomas to radiotherapy.

[Legal questions in radio-oncology. Demands on patient information and documentation of the therapy with examples of current legal cases concerning specialization in radiotherapy/radio-oncology]. / Rechtsfragen in der Radioonkologie. Anforderungen an das Aufklärungsgespräch und die Dokumentation der Behandlung mit Fallbeispielen aus der aktuellen Rechtsprechung für das Fachgebiet Strahlentherapie-Radioonkologie.

BACKGROUND: In recent years, also due to the media, the medical information a physician gives to his patients, the methods of medical treatment and their consequences have increasingly come to the attention of the general public. As a result, to avoid claims for compensation because of faulty treatment or even to evade prosecution, the demands on medical information given before or during treatment are getting greater and greater. Generally, claims for compensation are not based on the accusation of wrong treatment, because this accusation is difficult to prove. As a rule-as a way out of difficulties-these claims for compensation are based on the accusation of mistaken or incomplete information, because if one cannot prove any wrong treatment, faulty information can (nearly) always be proven. METHODS: Methodically, showing the principles that must be followed when giving information on radiotherapy and when documenting it, also taking examples of current legal cases into account. Short survey of the question of liability and the future importance of principles for medical treatment. CONCLUSION: Every attending physician should feel obliged to pay attention to legal questions concerning medical subjects, though judgments on the contents and the extent of the information that must be given to patients are complex and difficult to understand for anybody not experienced in law. Only so the ever-increasing tendency of people to try to make financial profit on information that they consider mistaken or incomplete can be opposed and a lawsuit can be won, if it cannot be avoided.

[Time factor and repopulation during fractionated radiotherapy. Comparison between two xenografted human squamous cell carcinoma]. / Zeitfaktor und Tumorrepopulierung während einer fraktionierten Radiotherapie. Vergleich zweier xenotransplantierter Plattenepithelkarzinome.

BACKGROUND: A series of experiments were performed to determine the local tumour control of two human squamous cell carcinoma lines in nude mice. An accelerated-fractionated radiation therapy regime is compared to a conventional-fractionated therapy regime. MATERIAL AND METHODS: KB is a well established human nasopharyngeal squamous cell carcinoma line (ATCC CCL 17). In nude mice KB grows as an low differentiated carcinoma. PEC MB is an undifferentiated squamous cell carcinoma of the maxillary sinus, which was successfully established in nude mice by our group 1993. Both tumors were serially passaged in nude mice. Local irradiation was given without anaesthesia under ambient conditions to air breathing animals using 18 MeV electrons of an linear accelerator (Mevatron 77, Siemens, Munich). Each dose level group consists of six to eight animals. The radiation treatments were given in ten equals fractions using graded dose levels of 2, 3, 4.5, 6 and 8 Gy. The interfraction time interval was 6 hours in the accelerated-fractionated group and 24 hours in the conventional-fractionated group (Figure 1). In the conventional-fractionated group a therapy break was given after 5 fractions for 72 h. The endpoint of the experiments was the dose, which was necessary to control 50% of the tumors (TCD(50)). The TCD(50) values were calculated after 60 days (Tables 1a and 1b). RESULTS: The experiments show, that with increasing overall treatment time of 8 3/4 days using the same number of fractions under ambient conditions the tumor control dose of the tumor KB increases from 36.3 Gy (95% CI 30.9...42.7) to 44.3 Gy (38.3...51.2) (Figure 2a). For the tumor PEC MB the tumor control dose increases from 39.5 Gy (33.4...46.7) to 45.5 Gy (37.0...56.0 (Figure 2b). CONCLUSION: This observed increase of the dose necessary to control the squamous cell carcinoma KB and PEC MB can be caused by repopulation of clonogenic tumors cells, however, other mechanism such as an increasing fraction of hypoxic tumor cells can not be ruled out.

Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials.

PURPOSE: The impact of different local therapy approaches on local control, event-free survival, and secondary malignancies in the CESS 81, CESS 86, and EICESS 92 trials was investigated. METHODS AND MATERIALS: The data of 1058 patients with localized Ewing tumors were analyzed. Wherever feasible, a surgical local therapy approach was used. In patients with a poor histologic response or with intralesional and marginal resections, this was to be followed by radiotherapy (RT). In EICESS 92, preoperative RT was introduced for patients with expected close resection margins. Definitive RT was used in cases in which surgical resection seemed impossible. In CESS 81, vincristine, adriamycin, cyclophosphamide, and actinomycin D was used. In CESS 86, vincristine, adriamycin, ifosfamide, and actinomycin D was introduced for patients with central tumors or primaries >100 cm(3). In CESS 92, etoposide, vincristine, adriamycin, ifosfamide, and actinomycin D was randomized against vincristine, adriamycin, ifosfamide, and actinomycin D in patients with primaries >100 cm(3). RESULTS: The rate of local failure was 7.5% after surgery with or without postoperative RT, and was 5.3% after preoperative and 26.3% after definitive RT (p = 0.001). Event-free survival was reduced after definitive RT (p = 0.0001). Irradiated patients represented a negatively selected population with unfavorable tumor sites. Definitive RT showed comparable local control to that of postoperative RT after intralesional resections. Patients with postoperative RT had improved local control after intralesional resections and in tumors with wide resection and poor histologic response compared with patients receiving surgery alone. Patients with marginal resections with or without postoperative radiotherapy showed comparable local control, yet the number of patients with good histologic response was higher in the latter treatment group (72.2% vs. 38.5%). CONCLUSION: Patients with resectable tumors after initial chemotherapy had a low local failure rate. With preoperative RT, local control was comparable. RT is indicated to avoid intralesional resections. After intralesional or marginal resections and after a poor histologic response and wide resection, postoperative RT may improve local control.

Radiation-induced changes of telomerase activity in a human Ewing xenograft tumor.

AIM: The effect of ionizing irradiation on telomerase activity and further associated biological factors was evaluated in a human Ewing tumor xenograft model on nude mice. MATERIAL AND METHODS: The human Ewing tumor cell line STA-ET-1 was established in a nude mouse model. Initially, the dose-response relationship for the tumor model was established. For the radiation experiments two dose levels were chosen: 5 Gy and 30 Gy. After 5 Gy, there was no significant growth delay whereas after 30 Gy there was a marked growth delay without the induction of a complete remission. Tumors were examined 6, 12, 24, 48, 72, and 96 hours post irradiation. After irradiation with 30 Gy further time points were 6, 9, 12 and 15 days. For each dose and time group, three tumors were evaluated. RESULTS: There was a reduction of telomerase activity after 5 Gy to 50% (not statistically significant) after 3 days; however, after 30 Gy there was a reduction of telomerase activity to 23% of the initial value after 6 days (p = 0.001). Telomerase activity correlated with the expression of human telomerase reverse transcriptase (hTERT), but not with the expression of telomerase-associated protein (TP1) and human telomerase RNA (hTR). The maximal amounts of necrosis or apoptosis after 30 Gy were 19% and 6.9%, respectively. CONCLUSIONS: Ionizing radiation reduces telomerase activity and the expression of hTERT which cannot be explained by the induction of necrosis or apoptosis alone. The reduction of telomerase activity may contribute to delayed cell death after radiotherapy. The combined use of radiation and specific telomerase inhibitors may be a potentially synergistic treatment strategy.