Search

Purpose: Stereotactic radiotherapy (SRT) is the predominant method for the irradiation of resection cavities after resection of brain metastases (BM). Intraoperative radiotherapy (IORT) with 50 kV x-rays is an alternative way to irradiate the resection cavity focally. We have already reported the outcome of our first 40 IORT patients treated until 2020. Since then, IORT has become the predominant cavity treatment in our center due to patients´ choice., Methods: We retrospectively analyzed the outcomes of all patients who underwent resection of BM and IORT between 2013 and August 2023 at Augsburg University Medical Center (UKA)., Results: We identified 105 patients with 117 resected BM treated with 50 kV x-ray IORT. Median diameter of the resected metastases was 3.1 cm (range 1.3 - 7.0 cm). Median applied dose was 20 Gy. All patients received standardized follow-up (FU) including three-monthly MRI of the brain. Mean FU was 14 months, with a median MRI FU for patients alive of nine months. Median overall survival (OS) of all treated patients was 18.2 months (estimated 1-year OS 57.7%). The observed local control (LC) rate of the resection cavity was 90.5% (estimated 1-year LC 84.2%). Distant brain control (DC) was 61.9% (estimated 1-year DC 47.9%). Only 16.2% of all patients needed WBI in the further course of disease. The observed radio necrosis rate was 2.6%., Conclusion: After 117 procedures IORT still appears to be a safe and appealing way to perform cavity RT after neurosurgical resection of BM with low toxicity and excellent LC., (© 2024. The Author(s).)

Introduction: The reconstruction of frontobasal defects following oncologic resections of paranasal and anterior skull base (ASB) malignancies remains challenging. Ineffective reconstruction could lead to cerebrospinal fluid leak, meningitis, and tension pneumocephalus., Research Question: Aim of this investigation was to analyse postoperative complication rates with or without bone graft for anterior skull base reconstruction., Material and Methods: In this retrospective study, we included patients following resection of paranasal and/or anterior skull base malignancies between October 2013 and December 2022. Complications were analysed with regards to the type of skull base reconstruction., Results: Eleven patients were identified (2 female, 9 male, age (median, SD) 64 ± 14.1 years (range 38-81). There were nine cases of paranasal sinus and nasal cavity carcinomas and two cases of olfactory neuroblastomas. Overall survival was 22.5 ± 28 months (range: 5-78), progression free survival was 17.0 ± 20.3 months (range: 11-78). Bone skull base reconstruction using a split graft was performed in three cases. Postoperative complications requiring surgical intervention were seen in 33% (one tension pneumocephalus) of cases in the bone reconstruction group and 50% (three patients with cerebrospinal fluid leak, one infection) in the non-bone reconstruction group., Discussion and Conclusion: The structural reinforcement of structural bone chip grafting might provide additional support of the ASB and prevent CSF leakage or encephalocele. Especially in large (>10 cm 2 ) bone defects of advanced sinonasal malignancies extending into the middle cranial fossa, the full armamentarium of reconstruction possibilities should be considered., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Purpose: Does focal cavity radiotherapy after resection of brain metastasis "spare" whole-brain radiotherapy, which is associated with toxicity for patients, through the complete course of their disease without compromising long-term local control of the brain?, Methods: We retrospectively analyzed outcomes of patients who underwent adjuvant focal cavity radiotherapy between 2014 and 2021 at our center., Results: A total of 83 patients with 86 resected brain metastases were analyzed. 64% had singular, 36% two to four brain metastases. In cases with multiple metastases, omitted lesions were treated with radiosurgery. Median follow-up was 7.3 months (range 0-71.2 months), 1‑year overall survival rate was 57.8% (95% CI 44.9-68.8%). Radiotherapy was administered with a median biologically effective dose (α/β 10) surrounding the planning target volume of 48 Gy (range 23.4-60 Gy). Estimated 1‑year local control rate was 82.7% (95% CI 67.7-91.2%), estimated 1‑year distant brain control rate was 55.7% (95% CI 40.5-68.4%), estimated 1‑year leptomeningeal disease rate was 16.0% (95% CI 7.3-32.9%). Eleven distant brain recurrences could be salvaged with radiosurgery. In the further course of disease, 14 patients (17%) developed disseminated metastatic disease in the brain. Estimated 1‑year free of whole-brain radiotherapy rate was 72.3% (95% CI 57.1-82.9%). All applied treatments led to an estimated 1‑year neuro-control rate of 79.1% (95% CI 65.0-88.0%), estimated 1‑year radionecrosis rate was 23% (95% CI 12.4-40.5%)., Conclusion: In our single-center study, focal cavity radiotherapy was associated with high local control. In three out of four patients, whole-brain radiotherapy could be avoided in the complete course of disease, using radiosurgery as salvage approach without compromising neuro-control., (© 2022. The Author(s).)

Awake craniotomies are performed to avoid postoperative neurological deficits when resecting lesions in the eloquent cortex, especially the speech area. Intraoperative radiotherapy (IORT) has recently focused on optimizing the oncological treatment of primary malignant brain tumors and metastases. Herein, for the first time, we present preliminary results of IORT in the setting of awake craniotomies. From 2021 to 2022, all patients undergoing awake craniotomies for tumor resection combined with IORT were analyzed retrospectively. Demographical and clinical data, operative procedure, and treatment-related complications were evaluated. Five patients were identified (age (mean ± standard deviation (SD): 65 ± 13.5 years (y)). A solid left frontal metastasis was detected in the first patient (female, 49 y). The second patient (male, 72 y) presented with a solid metastasis on the left parietal lobe. The third patient (male, 52 y) was diagnosed with a left temporoparietal metastasis. Patient four (male, 74 y) was diagnosed with a high-grade glioma on the left frontal lobe. A metastasis on the left temporooccipital lobe was detected in the fifth patient (male, 78 y). After awake craniotomy and macroscopic complete tumor resection, intraoperative tumor bed irradiation was carried out with 50 kV x-rays and a total of 20 Gy for 16.7 ± 2.5 min. During a mean follow-up of 6.3 ± 2.6 months, none of the patients developed any surgery- or IORT-related complications or disabling permanent neurological deficits. Intraoperative radiotherapy in combination with awake craniotomy seems to be feasible and safe., (© 2022. The Author(s).)

The new Medical Licensing Regulations 2025 (Ärztliche Approbationsordnung, ÄApprO) will soon be passed by the Federal Council (Bundesrat) and will be implemented step by step by the individual faculties in the coming months. The further development of medical studies essentially involves an orientation from fact-based to competence-based learning and focuses on practical, longitudinal and interdisciplinary training. Radiation oncology and radiation therapy are important components of therapeutic oncology and are of great importance for public health, both clinically and epidemiologically, and therefore should be given appropriate attention in medical education. This report is based on a recent survey on the current state of radiation therapy teaching at university hospitals in Germany as well as the contents of the National Competence Based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog Medizin 2.0, NKLM) and the closely related Subject Catalogue (Gegenstandskatalog, GK) of the Institute for Medical and Pharmaceutical Examination Questions (Institut für Medizinische und Pharmazeutische Prüfungsfragen, IMPP). The current recommendations of the German Society for Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO) regarding topics, scope and rationale for the establishment of radiation oncology teaching at the respective faculties are also included., (© 2021. The Author(s).)

Purpose: External-beam radiotherapy (EBRT) is the predominant method for localized brain radiotherapy (LBRT) after resection of brain metastases (BM). Intraoperative radiotherapy (IORT) with 50-kV x‑rays is an alternative way to focally irradiate the resection cavity after BM surgery, with the option of shortening the overall treatment time and limiting normal tissue irradiation., Methods: We retrospectively analyzed the outcomes of all patients who underwent neurosurgical resection of BM and 50-kV x‑ray IORT between 2013 and 2020 at Augsburg University Medical Center., Results: We identified 40 patients with 44 resected BM treated with 50-kV x‑ray IORT. Median diameter of the resected metastases was 2.8 cm (range 1.5-5.9 cm). Median applied dose was 20 Gy. All patients received standardized follow-up (FU) including 3‑monthly MRI of the brain. Mean FU was 14.4 months, with a median MRI FU for alive patients of 12.2 months. Median overall survival (OS) of all treated patients was 26.4 months (estimated 1‑year OS 61.6%). The observed local control (LC) rate of the resection cavity was 88.6% (estimated 1‑year LC 84.3%). Distant brain control (DC) was 47.5% (estimated 1‑year DC 33.5%). Only 25% of all patients needed WBI in the further course of disease. The observed radionecrosis rate was 2.5%., Conclusion: IORT with 50-kV x‑rays is a safe and appealing way to apply LBRT after neurosurgical resection of BM, with low toxicity and excellent LC. Close MRI FU is paramount to detect distant brain failure (DBF) early., (© 2021. The Author(s).)

Introduction: Esophageal cancer (EC) is a common malignant tumor entity with increasing occurrence. The incidence of esophageal adenocarcinoma (AC), particularly, is constantly rising in the Western world. The mainstays of therapy with curative intent for EC in advanced stages are neoadjuvant radiochemotherapy (neoRCT) with surgery and definitive radiochemotherapy (defRCT)., Methods: We examined our internal files to identify patients suffering from EC. Palliative cases were excluded. Statistical testing was performed by χ2 test, Student's t test, Kaplan-Meier analyses, and the Mann-Whitney U test., Results: One hundred and twenty-two cases were included. Histology revealed squamous cell carcinoma in 92 cases and AC in 23 cases. Ninety-five patients underwent defRCT, 27 underwent neoRCT, and 114 (in both therapy regimes) received simultaneous chemotherapy. There was no difference in the overall survival (OS) (p = 0.654; HR 1.145; 95% CI 0.629-2.086) or and progression-free survival (PFS) (p = 0.912) of patients who underwent neoRCT or defRCT. Median OS was 13.5 (2-197) months for defRCT patients and 19.5 (2-134) months for neoRCT patients (p = 0.751). Karnofsky index (KI) with a cut-off of 70% was strongest, but not a significant parameter for OS (p = 0.608) or PFS (p = 0.137)., Conclusion: defRCT is a valid and an equal alternative to neoRCT for patients suffering from EC. Selection of patients for therapy is of crucial relevance. Further studies and improvements in follow-up are needed when neoRCT has been completed before surgery, in order to spare the patient undergoing operative treatment if there is complete remission. The identification of valid markers urgently needed to limit treatment side effects., (© 2020 S. Karger AG, Basel.)

Purpose: Long-term impact of stage-adapted field reduction in a large cohort of gastric marginal zone lymphoma (gMZL) patients treated conservatively with curative radiation therapy (RT)., Patients and Methods: Prospective analysis of paper records of 290 patients with stage IE-IIE gMZL, treated in 78 radiotherapeutic institutions in Germany from 1992-2013. Stage-adapted radiation fields decreased from extended field (EF) to involved field (IF) over the course of three consecutive prospective trials of the German Study Group on Gastrointestinal Lymphoma (DSGL). Treatment results were compared between the three cohorts., Results: Overall collective with median age of 60 years, slight male predominance (m:f = 1.1:1) and ratio of disease stage I:stage II = 2.1:1. Median follow-up 6.4 years in total: 13.0 years in the first gastrointestinal study (GIT 1992), 8.2 years in the second (GIT 1996) and 4.7 years in the third study (DSGL 01/2003). Stage-adapted radiation field decrease together with further technological development led to reduced relative frequencies of acute/chronic adverse effects and until now was accompanied by lower disease recurrence. The third study design with smallest field size (IF in stage I, locoregional EF in stage II) achieved the best survival outcome at the 5‑year follow-up (overall survival 92.7%, event-free survival 89.5% and lymphoma-specific survival 100.0%). Disease relapse observed in 10 patients. Cumulative incidence of disease-specific death was 1.7% of the followed patients. Primary disease stage associated with lymphoma-specific survival., Conclusion: Stage-adapted reduction towards IF in gMZL resulted in favorable adverse effects, local control and survival rates. These results support further decreases in modern RT of gMZL.

Objective: Hyperfractionated accelerated radiotherapy (HART) has been combined with chemotherapy (CC) for locally advanced head and neck cancer, but no data from randomized trials are available for a comparison with conventionally fractionated radiotherapy (CFRT) and CC., Methods: This monoinstitutional retrospective study compares the results of both treatment schedules: 315 patients with locally advanced carcinoma (UICC stage III and IV) of the oral cavity and the orohypopharynx were treated from January 1990 to March 2006 with a radiochemotherapy combination based on mitomycin C and fluorouracil (HART-CC: 203 patients, CFRT-CC: 112 patients, total dose: 70-72 Gy) with curative intent., Results: Two- and 4-year survival was 60 and 42 (HART-CC) and 59 and 42% (CFRT-CC; p = 0.82, log-rank test), respectively. Using multivariate Cox regression, pretreatment hemoglobin level, N stage, tumor site but not the year of treatment, gender and T stage were significant prognosticators for survival. For locoregional control, only N stage was significant. The prognostic value of these pretreatment factors did not variate with the fractionation schedule used., Conclusions: In combination with CC, there was no trend towards an improved efficacy of HART in comparison with CFRT., (Copyright 2009 S. Karger AG, Basel.)

Purpose: To investigate the role of prophylactic cranial irradiation (PCI) within a trimodality protocol (chemotherapy, chemoradiotherapy, surgery) for patients with operable stage IIIA non-small-cell lung cancer (NSCLC)., Patients and Methods: After mediastinoscopic staging, patients with operable stage IIIA NSCLC were enrolled to a German multicenter trial and randomly assigned to receive either primary resection followed by adjuvant thoracic radiation therapy (50 to 60 Gy; arm A) or preoperative chemotherapy (cisplatin/etoposide [PE]; three cycles) followed by concurrent chemoradiotherapy (PE plus 45 Gy; 1.5 Gy twice per day) and definitive surgery (arm B), respectively. Patients in arm B were scheduled to receive PCI (30 Gy; 2 Gy daily fractions)., Results: One hundred twelve patients were randomly assigned between November 1994 and July 2001. One hundred six patients were eligible (arm A: 51, arm B: 55), 90 males and 16 females, 50 with squamous cell, 16 with large cell, five with adenosquamous, and 35 with adenocarcenoma (median age, 57 years; range, 37 to 71 years). Forty-three patients received PCI as scheduled in arm B. Eleven long-term survivors (arm A: four; arm B: seven) underwent a comprehensive neuropsychological examination. PCI significantly reduced the probability of brain metastases as first site of failure (7.8% at 5 years v 34.7%; P = .02), the overall brain relapse rate was reduced comparably (9.1% at 5 years v 27.2%; P = .04). A slightly reduced neurocognitive performance in comparison with the age-matched normal population was found for patients in both treatment groups. No significant difference between patients who were treated with or without PCI could be noted., Conclusion: PCI is effective in preventing brain metastases following this aggressive trimodality approach. Neurocognitive late effects are not significantly different between patients treated with or without PCI.

The implantation of tumour cells in normal tissues and the subsequent induction of angiogenesis by the growing xenograft were studied by means of immunohistochemistry and digital image analysis. Tumour growth was induced by injection of a human spindle cell sarcoma (ES3) into the subcutis of HsdCpb:NMRI-nu/nu mice. In vivo injection of Hoechst 33342 was used as a marker of perfusion. The vasculature was stained with specific antibodies and subsequently analysed by digital image analysis. Starting at day 3 up to day 6, angiogenesis could be detected and the relative amount of perfusion within the investigated area reached a peak at day 6. This method, which allows investigation of both functional and morphometric characteristics of human xenograft vasculature, serves as an excellent assay for evaluation of antiangiogenic therapies in translational research of experimental tumours.

Lung cancer is difficult to control locally by radiotherapy and is known to have frequently p53 mutations. Previous results have shown that non-small-cell lung cancer (NSCLC) cell lines with nonfunctional p53 have a higher fraction of radiation-induced apoptosis and that apoptosis follows after the release from the G2/M arrest. The aim of the present work was to study whether inhibition of the p53 response in NSCLC cell lines can modulate the G2/M arrest and the induction of apoptosis after ionizing radiation. Antisense oligodeoxynucleotides (As-ODNs) were used to inhibit the p53 response in the cell lines H460 and A549 with functional p53. In addition, H661 with nonfunctional p53 was used. The results have shown that As-ODNs targeting mRNA of p53 and p21 downregulate radiation-induced expression of p53 and p21(WAF1/CIP1). Delayed apoptosis (35.7+/-4.2% in H460, 1.2+/-0.4% in A549 and 72.2+/-6.5% in H661) was observed after cell cycle progression beyond the G2 block, either in the late G2 phase of the same cell cycle being irradiated (H661) or in the G1 phase of the subsequent cell cycle (H460, A549). As-p53 significantly decreased the fraction of G2/M-arrested cells in H460 cells and increased radiation-induced apoptosis at 96 hours by 17.9+/-8.5 and 9.1+/-3.3% to 53.6+/-7.4 and 10.8+/-2.9% in H460 and A549 cells (P<.01), respectively, but had no effect in H661 cells with nonfunctional p53. In addition, As-p21 decreased the fraction of G2-arrested A549 and H460 cells and increased apoptosis by 23.8+/-5.2 and 31.6+/-7.3% to 59.4+/-3.1 and 32.8+/-7.3%, respectively (P<.01). In conclusion, these data show that radiation-induced G2 arrest is decreased in NSCLC cells and radiation-induced apoptosis is increased when p53-responsive pathways are blocked via As-ODN targeting p53 or p21(WAF1/CIP1) mRNA. In view of the fact that p53 and p21 As-ODN had similar effects on radiation-induced apoptosis normalized by their ability to inhibit radiation-induced p21 expression, we concluded that p21 is an important trigger of late ionizing radiation-induced apoptosis.

In spite of aggressive therapy, children suffering from neuroblastoma have a poor prognosis. Therapeutic failure is most often observed in neuroblastomas with unfavorable features, including amplification/over-expression of the N-myc oncogene, rapid growth, effective angiogenesis and/or the tendency to metastasize. Here, we have used cultured human neuroblastoma cells with such features and we have examined whether antiangiogenic agents alone or in combination with tumor irradiation inhibit their angiogenesis and growth in vivo. We report that antiangiogenic agents (arginine deiminase, SU5416 and DC101) inhibit in vivo growth of neuroblastomas with unfavorable properties and that these effects are potentiated by simultaneous irradiation. Combination of either agent with irradiation leads to a reduction in the absolute number of tumor vessels and of perfused tumor vessels. Combination of arginine deiminase or DC101 with irradiation does not increase tumor hypoxia. Our data demonstrate for the first time that arginine deiminase suppresses the growth of unfavorable experimental neuroblastomas and that this effect is potentiated by irradiation. We suggest that antiangiogenesis alone or in combination with established therapeutic regimen may improve the outcome of unfavorable neuroblastomas in a clinical setting., (Copyright 2003 Wiley-Liss, Inc.)

Purpose: To analyze the long-term results following whole brain radiotherapy (WBRT) with sequential intrathecal (i.th.) cytosine arabinoside (Ara-C) +/- intravenous (i.v.) Ara-C in patients with primary central nervous system lymphoma (PCNSL)., Patients and Methods: 14 patients were treated between July 1987 and August 1995. All had sporadic PCNSL with proven histology of high-grade CNS lymphoma (twelve diffuse large-cell B-lymphomas, one lymphoblastic lymphoma, one large T-cell lymphoma). Patients were treated with two to four cycles of induction chemotherapy (40 mg/m2 Ara-C i.th.), four patients received additional Ara-C i.v. (150 mg/m2, d1-4). WBRT was administered using 1.8-Gy fractions. Intrathecal chemotherapy was planned afterwards in 4-week intervals for 6 months. Posttreatment neurocognitive evaluations were performed in two long-term survivors., Results: Two of four patients who received i.v. and i.th. induction chemotherapy showed progressive disease, and irradiation was started immediately. Six of 14 patients received 50.4 Gy WBRT, four patients had WBRT up to 39.6 Gy followed by a 10.8-Gy boost. Five patients died early during therapy either due to a decline of the general medical condition or progressive disease. Median survival was 41 months (95% confidence interval: 6-79 months), survival at 3 and 5 years was 59% and 42%, respectively. Six patients survived for 3 years, two younger patients are still alive (> 12 years). They show only slightly impaired neurocognitive functions without clinical relevance., Conclusion: This WBRT-based protocol with i.th. meningeal prophylaxis using Ara-C +/- i.v. Ara-C yields substantial long-term survival with moderate toxicity. The value of i.v. chemotherapy is currently being investigated in prospective studies.

Background: Pronounced oxygen deficiency in tumors which might be caused by a diminished oxygen transport capacity of the blood (e.g., in anemia) reduces the efficacy of ionizing radiation. The aim of this study was to analyze whether anemia prevention by recombinant human erythropoietin (rHuEPO) affects the radiosensitivity of human glioblastoma xenografts during fractionated irradiation., Material and Methods: Anemia was induced by total body irradiation (TBI, 2 x 4 Gy) of mice prior to tumor implantation into the subcuts of the hind leg. In one experimental group, the development of anemia was prevented by rHuEPO (750 U/kg s.c.) given three times weekly starting 10 days prior to TBI. 13 days after tumor implantation (tumor volume approx. 40 mm3), fractionated irradiation (4 x 7 Gy, one daily fraction) of the glioblastomas was performed resulting in a growth delay with subsequent regrowth of the tumors., Results: Compared to nonanemic control animals (hemoglobin concentration cHb = 14.7 g/dl), the growth delay in anemic mice (cHb = 9.9 g/dl) was significantly shorter (49 +/- 5 days vs. 79 +/- 4 days to reach four times the initial tumor volume) upon fractionated radiation. The prevention of anemia by rHuEPO treatment (cHb = 13.3 g/dl) resulted in a significantly prolonged growth delay (61 +/- 5 days) compared to the anemia group, even though the growth inhibition found in control animals was not completely achieved., Conclusions: These data indicate that moderate anemia significantly reduces the efficacy of radiotherapy. Prevention of anemia with rHuEPO partially restores the radiosensitivity of xenografted glioblastomas to fractionated irradiation.

Purpose: The effect of recombinant human erythropoietin (rhEPO) on the radiosensitivity of human tumor xenografts growing in anemic and nonanemic nude mice was studied., Methods and Materials: Anemia was induced by total body irradiation ([TBI], 2 x 4 Gy) of mice before tumor implantation into the subcutis of the hind leg. The development of anemia was prevented by rhEPO (750 U/kg s.c.) given 3 times weekly starting 2 weeks before TBI. Fourteen days after fractionated TBI (tumor volume of approx. 40 mm(3)), single-dose irradiation of the tumor with varying doses was performed so that in full dose-response relationship for the probability of tumor cure was obtained., Results: Radiation-induced anemia (hemoglobin concentration [cHb] = 9.9 g/dl) led to a reduced radiosensitivity compared to controls [49.4 vs. 40.1 Gy radiation dose to control 50% of the tumors (TCD50)]. Upon rhEPO treatment for anemia prevention (cHb = 13.3 g/dl), the TCD50 was 39.8 Gy, illustrating restored radiosensitivity compared to anemic mice., Conclusion: These data provide further experimental evidence for restored radiosensitivity upon prevention of anemia with rhEPO.

The European Organization for Research and Treatment of Cancer (EORTC) 22861 randomised trial established that combined radiochemotherapy is the standard treatment for locally advanced anal cancer. This EORTC phase II study (#22953) tests the feasibility of reducing the gap between sequences to 2 weeks, to deliver Mitomycin C (MMC) in each radiotherapy sequence and 5-FU continuously during the treatment. The first sequence consisted of 36 Gy over 4 weeks. 5-FU 200 mg/m(2)/days 1-26, MMC 10 mg/m(2)/day 1 gap 16 days. Then a second sequence of 23.4 Gy over 17 days, 5-FU 200 mg/m(2)/days 1-17 and, MMC 10 mg/m(2)/day 1 was given. 43 patients with a World Health Organization (WHO) status of 0 (n=27) or 1 (n=16) and with T2-T4, N0-3 tumours were included. Compliance with the planned treatment, doses and duration was 93%. The complete response rate was 90.7%. Grade 3 toxicities of 28, 12 and 2% were observed for skin, diarrhoea and haematological toxicities, respectively. The 3-year estimated rates for trials 22861 and 22953 are: 68 and 88% for local control; 72 and 81% for colostomy-free interval, 62 and 84% for severe late toxicity-free interval, and 70 and 81% for survival, respectively. The 22953 scheme is feasible and the results are promising. This is now considered as the new standard scheme by the EORTC.

Purpose: To characterize the relationship between cell-cycle progression and radiation-induced apoptosis in NSCLC cell lines with different p53 status., Materials and Methods: Cell lines with functional (H460, A549) and non-functional p53 (H661 and H520) were irradiated with 20 Gy. Multiparameter flow-cytometry was used to follow the progression of synchronized cells through the cell cycle after irradiation., Results: Delayed apoptosis was observed after cell-cycle progression beyond the G2 block, either in the late G2/M-phase of the same cell cycle being irradiated (H661, H520) or in the G1-phase of the subsequent cell cycle (H460, A549). The apoptotic fraction in H661 and H520 was 60-80% at 144h after irradiation, higher than in A549 and H460 (5 and 35%, respectively). As an alternative to apoptosis in cells cycling beyond the G2 restriction point, hyperploid cells were generated by all cell lines. Inhibition of cell-cycle progression through the G2/M-phase efficiently reduced the induction of late apoptosis. After irradiation in S-phase, 50-60% of cells with functional p53 remained arrested at the G2 restriction point until 144 h post-irradiation, while only 20% of the H661 or H520 did so., Conclusions: These data characterize radiation-induced apoptosis in NSCLC cell lines as a removal pathway of clonogenically inactivated cells secondary to cell-cycle progression beyond G2/M, and is unlikely to be a critical factor for cellular radiation sensitivity.

Background: Overall prognosis of patients with locally advanced non-small-cell lung cancer (LAD-NSCLC) is still unfavourable. Different attempts to improve treatment results have been made using combinations of chemotherapy and radiotherapy. The aim of this pilot phase I/II investigation was to test the feasibility and toxicity of a definitive multimodality protocol in patients with irresectable NSCLC stages IIIA (N2) and IIIB., Patients and Methods: Thirty LAD-NSCLC patients (stages IIIA/IIIB: 3/27; median age: 54 years, range 34-70; male/female: 17/13) who were consecutively enrolled onto our ongoing neoadjuvant multimodality protocol from October 1996 to February 1999 remained inoperable after induction treatment. Three cycles of cisplatin/etoposide (PE) were followed by hyperfractionated accelerated radiotherapy (HF-RTx: 1.5 Gy bid up to a total dose of 45 Gy in 3 weeks) concurrent with one cycle of PE. Definitive local treatment was completed with a small volume boost of 20 Gy (qd), adding up to a total dose of 65 Gy to the primary. Patients were routinely offered prophylactic cranial irradiation (PCI; 30 Gy; 2 Gy qd)., Results: Overall toxicity of the definitive CTx/RTx protocol-the main endpoint of this investigation-turned out to be acceptable (oesophagitis grade 3/4: 6/4 patients; pneumonitis grade 3/4: 0/1 patients; no treatment-related deaths). Actuarial survival at 2 years was 31% with a loco-regional control rate of 21%., Conclusions: This regimen turned out to be feasible with acceptable toxicity and will serve as a reference arm in a planned randomised trial in stage IIIB NSCLC, testing the value of surgery in this setting: preoperative induction CTx/RTx followed by surgery versus definitive CTx/RTx.

Background: Local recurrence of nasopharyngeal carcinomas can be treated in different ways. One option is re-irradiation e. g. as stereotactically guided convergent beam. An operative approach is possible in small recurrent tumours. Brachytherapy is a good alternative because of the steep dose gradient in the pre-irradiated area., Methods: First step is the creation of a wide approach to the nasopharynx. This leads to a tumour mass reduction and gives space for the applicator. The radioactive substance will be brought into contact with the tumour by an afterloading procedure. The advantage of this therapy is the possibility to protect the surrounding tissue whereas the tumour receives a relatively high dosage. Between 2/90 and 12/96 10 men and 3 women were treated according to this protocol., Results: The median age was 56 years (37- 66 years), the average follow-up period was 49,7 months (8 -123 months). 2 non keratinising and 11 undifferentiated carcinomas were treated. 5 of 13 patients were still alive at the end of the follow-up period. The 5 year over all survival rate was 46 %. 3 patients are free of disease for 5 years or longer. The patients were treated 2 to 6 times with 7 Gy in 5 mm depth., Conclusions: The results show that good palliation can be achieved by the applied method but larger studies are required to give a definite statement.

Purpose: The incidence of nasopharyngeal carcinoma in Germany is relatively low in comparison with certain regions in south-east Asia. However, standardised therapeutical regimes are required in the treatment of these tumours., Methods: Between August 1990 and December 1997, 25 patients with stage III and IV nasopharyngeal carcinoma received an accelerated and hyperfractionated radiotherapy with concurrent chemotherapy (5-FU and mitomycin C). The primary tumour and positive lymph nodes received a total dose of 72 Gy over a period of 6 weeks. In the first 3 weeks, irradiation fields were treated five times per week with 2 Gy per fraction. Thereafter, treatment was accelerated, giving two daily fractions of 1.4 Gy. Salvage surgery was offered for residual lymph node disease after radiotherapy., Results: The overall response rate defined as complete and partial response of the primary was 100%. Sixteen of the 25 patients were still alive and were free of any evidence of tumour recurrence or distant metastases at a mean follow-up period of 34 months (range 7-95 months). Six patients received salvage surgery. Only one of these six patients had histologically proven evidence of vital tumour. No severe late complications such as blindness or temporal lobe necrosis were observed., Conclusions: The presented data are promising and show that the combination of hyperfractionated accelerated radiotherapy and chemotherapy is feasible and effective.

Lymphocytes of healthy volunteers (n = 24) and of tumour patients (n = 30, 18 of whom had experienced severe side-effects) were irradiated with x-rays in vitro. DNA damage was analysed after 0.25-2 Gy and DNA repair after 2 Gy, and quantification of both endpoints was done by the comet assay. The individual differences in radiation-induced DNA damage as well as in the repair kinetics were observed to be striking for both healthy donors and tumour patients. After a repair time of 3 h, following 2 Gy x-irradiation, some of the healthy volunteers showed no residual DNA damage at all in their lymphocytes, whereas others revealed about 30%. There was no indication that our results were affected by either age, gender or smoking habits. Slow repair kinetics and high amounts of residual damage were characteristic for many but not all tumour patients who had experienced severe side-effects in their normal tissues during or after radiotherapy (n = 18). Our conclusion is that those individuals showing poor DNA repair characteristics in the lymphocytes following in vitro irradiation, have a high probability of being radiosensitive. The opposite conclusion is not necessarily true: if repair is effective, this does not mean that the individual is radioresistant, because factors other than impaired repair may cause radiosensitivity.

Patients with unfavorable stages of lung cancer are rarely cured with local treatment modalities alone. Aim of our phase II trial was to investigate the effectivity of a multimodality treatment. Ninety-four patients with NSCLC (stage IIIA/IIIB) were treated preoperatively with chemoradiotherapy (cisplatin and etoposide, 45 Gy hyperfractionated accelerated radiotherapy). After repeat mediastinoscopy patients underwent surgery. Complete resection (R0) was achieved in 53% of all patients with NSCLC. Two patients died of sepsis preoperatively and four postoperatively (90-days lethality: 6.4%). The median survival time was 20 months for IIIA and 18 months for IIIB. Calculated survival rates at 6 years were 34% for IIIA and 17% for IIIB. This multimodality treatment demonstrates high efficacy in prognostically unfavorable NSCLC compared with historical controls.

Purpose: The effect of recombinant human erythropoietin (Epo) on the radiosensitivity of human tumour xenografts growing in anaemic nude mice was studied., Methods and Materials: Anaemia was induced by total body irradiation (TBI) of mice prior to tumour transplantation. The development of anaemia was prevented by Epo (1000 U/kg s.c.) given 3 times weekly starting 2 weeks prior to TBI (5 Gy). Epo treatment did not influence the growth rate of the tumours, which were transplanted into the subcutis of the hind leg of mice. Thirteen days after TBI (tumour volume of approx. 40 mm3), a single-dose irradiation (12 Gy) of the tumour was performed resulting in a growth delay with subsequent regrowth of the tumours., Results: In Epo-treated animals the tumour growth delay was significantly longer compared to anaemic mice. However, the radiosensitivity of tumours in non-anaemic animals' (non-Epo-treated) tumours could not fully be restored., Conclusion: These data give evidence for restored radiosensitivity after correction of anaemia with Epo.

The purpose of this study was to evaluate the efficacy and toxicity of an induction chemotherapy schedule followed by high-dose radiotherapy and concurrent chemotherapy for locally advanced squamous cell carcinomas of the upper and midthoracic esophagus. Patients were treated with three courses of fluorouracil, leucovorin, etoposide, and cisplatin-containing induction chemotherapy followed by high-dose external beam radiotherapy to 65 Gy in 6 weeks for T4 and obstructing T3 tumors. Transversable T3 tumors received 60 Gy in 6 weeks by external radiotherapy, followed by two high-dose-rate esophageal brachytherapy fractions of 4 Gy in 5-mm tissue depth. Concurrent to radiotherapy, cisplatin and etoposide were given. Long-term survival of 22 patients was 41% and 31% at 2 and 3 years, respectively, with a median follow-up of 39 months. The probability of locoregional tumor recurrence was 60% at 3 years for all patients and 30% for those with a partial or complete response to induction chemotherapy. Acute toxicity of this schedule was moderate. Long-term survivors had a good swallowing function. This schedule offers a considerable chance of long-term survival for patients with locally advanced squamous cell carcinomas of the upper and midthoracic esophagus. Local in-field recurrences are the main risk after definitive radiochemotherapy. Dose escalation of radiotherapy is possible because of the observed low late toxicity.

Following mediastinoscopy, a prognostically orientated multimodality approach was chosen in selected small-cell lung cancer (SCLC) patients with hyperfractionated accelerated chemoradiotherapy (Hf-RTx) and definitive surgery (S). Stage IB/IIA patients had four cycles of cisplatin/etoposide (PE) and surgery. Stage IIB/IIIA patients had three cycles PE followed by one cycle concurrent chemoradiation including Hf-RTx and surgery. Most stage IIIB patients were not planned for surgery and had CTx followed by sequential RTx or one cycle concurrent CTx/RTx. Of 46 consecutive patients (stage IB six, IIA two, IIB/IIIA 22, IIIB 16) 43 (94%) showed an objective response. Twenty-three of patients (72%) planned for inclusion of S were completely resected (R0) (IB 6/6, IIA 2/2, IIB/IIIA 13/22, IIIB 2/2). Overall toxicity was acceptable--one patient died of septicaemia, no perioperative deaths occurred. Median follow-up of patients alive (n = 21) is 52 months (30+ - 75+). Median survival and 5-year survival rate of all patients are 36 months and 46%, in R0 patients 68 months and 63% (R0-IIB/IIIA/IIIB: not yet reached and 67%). This multimodality treatment including surgery proved highly effective with 100% local control and remarkable long-term survival after complete resection, even in locally advanced SCLC stages IIB/IIIA patients.

Purpose: During the last 20 years, evidence has been accumulating for the existence in animal and human tumors of quiescent S-phase cells, i.e. cells with an S-phase DNA content that do not actively synthesize DNA. In cell culture studies, quiescent S-phase cells have been observed under physiological conditions typical for poorly vascularized regions of tumors such as reduced pH, hypoxia, and glucose deprivation. Therefore, we studied the possible correlation between the frequency of quiescent S-phase cells and the oxygenation status as determined polarographically in a number of human tumor xenografts., Methods and Materials: Five human tumor xenografts on nude mice were used. Oxygenation was measured polarographically with an Eppendorf pO2-Histograph in 24 to 30 individual tumors for each entity. Mice were injected intraperitoneally with 1 mg/30 g bodyweight bromodeoxyuridine (BrdU), tumors were excised 30 min later and prepared into a single-cell suspension. After immunofluorescence staining with an antibody against BrdU and staining of the DNA with propidium iodide, cells were measured in a FACScan flow cytometer and the frequency of cells in the S-phase compartment that did not incorporate BrdU was determined., Results: In most cases, the frequency of measurements of an oxygen partial pressure <5 mm Hg in the tumor tissue increased with tumor volume. Likewise, the frequency of quiescent S-phase cells was generally higher in larger tumors. Taking all five tumor entities together, there was a highly significant correlation between tumor oxygenation and the occurrence of quiescent S-phase cells., Conclusions: Our data confirm earlier findings that inactive S-phase cells do exist in vivo. Because their frequency seems to be dependent (directly or indirectly) on the degree of oxygenation and has been shown to increase not only with hypoxia, but also with reduced pH and glucose deprivation in vitro, the frequency of inactive S-phase cells may be considered a summary indicator for extreme physiological conditions in tumors.

Background: Preoperative chemoradiotherapy is feasible for selected patients with non-small cell lung cancer stage IIIb. The aim of this investigation was to analyze long-term results after this multimodality approach and to identify subgroups with improved long-term prognosis., Methods: From March 1991 to June 1996, 56 patients were entered. Three cycles of cisplatin (P) (60 mg/m2, days 1 + 7) and etoposide (E) (150 mg/m2, days 3 to 5 qd 22) were followed by one cycle of radiotherapy/chemotherapy (RTx/CTx) (45 Gy, 1.5 Gy bid/3 weeks with P 50 mg/m2 days 2 + 9/E 100 mg/m2 days 4 to 6) followed by repeat mediastinoscopy and surgery., Results: There were 46 men and 10 women (age 34 to 69 years, median 55 years; World Health Organization status 0 to 2, median 1). Twenty-eight had T4, and 32 had proven N3, in detail: T4N0/1, 10; T4N2, 14; T3N3, 9; T4N3, 4; and T1/2N3, 19. Thirty-four (61%) were operated on; 27 (48%) were completely (R0) resected. Survival at 5 years is 26% for all, and 43% for R0 patients. Toxicity included two deaths (one septicemia, one anastomosis insufficiency)., Conclusions: This intensive program proved to be highly effective in unfavorable IIIB subgroups with promising long-term survival for T4 tumors as well as N3 disease.

Purpose: Relapse pattern and late toxicities in long-term survivors were analyzed after the introduction of prophylactic cranial irradiation (PCI) into a phase II trial on trimodality treatment of locally advanced (LAD) non-small-cell lung cancer (NSCLC)., Patients and Methods: Seventy-five patients with stage IIIA(N2)/IIIB NSCLC were treated with induction chemotherapy, preoperative radiochemotherapy, and surgery. PCI was routinely offered during the second period of study accrual. Patients were given a total radiation dose of 30 Gy (2 Gy per daily fraction) over a 3-week period starting 1 day after the last chemotherapy cycle., Results: Introduction of PCI reduced the rate of brain metastases as first site of relapse from 30% to 8% at 4 years (P =.005) and that of overall brain relapse from 54% to 13% (P <.0001). The effect of PCI was also observed in the good-prognosis subgroup of 47 patients who had a partial response or complete response to induction chemotherapy, with a reduction of brain relapse as first failure from 23% to 0% at 4 years (P =.01). Neuropsychologic testing revealed impairments in attention and visual memory in long-term survivors who received PCI as well as in those who did not receive PCI. T2-weighted magnetic resonance imaging revealed white matter abnormalities of higher grades in patients who received PCI than in those who did not., Conclusion: PCI at a moderate dose reduced brain metastases in LAD-NSCLC to a clinically significant extent, comparable to that in limited-disease small-cell lung cancer. Late toxicity to normal brain was acceptable. This study supports the use of PCI within intense protocols for LAD-NSCLC, particularly in patients with favorable prognostic factors.

Purpose: The aim of this study was to characterize and to validate noninvasive 19F-magnetic resonance relaxometry for the measurement of oxygen tensions in human glioma xenografts in nude mice. The following three questions were addressed: 1. When perfluorocarbon compounds (PFCs) are administrated intravenously, which tumor regions are assessed by 19F-MR relaxometry? 2. Are oxygen tension as detected by 19F-MR relaxometry (pO2/relaxo) comparable to Eppendorf O2-electrode measurements (pO2/electrode)? 3. Can 19F-MR relaxometry be used to detect oxygen tension changes in tumor tissue during carbogen breathing?, Methods and Materials: Slice-selective 19F-MR relaxometry was carried out with perfluoro-15-crown-5-ether as oxygen sensor. The PFC was injected i.v. 3 days before the 19F-MR experiments. Two datasets were acquired before and two after the start of carbogen breathing. The distribution of PFCs and necrotic areas were analyzed in 19F-Spin Echo (SE) density MR images and T2-weighted 1H-SE MR images, respectively. One day after the MR investigations, oxygen tensions were measured by oxygen electrodes in the same slice along two perpendicular tracks. These measurements were followed by (immuno)histochemical analysis of the 2D distribution of perfused microvessels, hypoxic cells, necrotic areas, and macrophages., Results: The PFCs mainly became sequestered in perfused regions at the tumor periphery; thus, 19F-MR relaxometry probed mean oxygen tensions in these regions throughout the selected MR slice. In perfused regions of the tumor, mean PO2/relaxo values were comparable to mean PO2/electrode values, and varied from 0.03 to 9 mmHg. Median pO2/electrode values of both tracks were lower than mean pO2/relaxo values, because low pO2 electrode values that originate from hypoxic and necrotic areas were also included in calculations of median pO2/electrode values. After 8-min carbogen breathing, the average PO2/relaxo increase was 3.3 +/- 0.8 (SEM) mmHg and 2.1 +/- 0.6 (SEM) after 14 min breathing., Conclusions: We have demonstrated that PFCs mainly became sequestered in perfused regions of the tumor. Here, mean PO2/relaxo values were comparable to mean PO2electrode values. In these areas, carbogen breathing was found to increase the PO2/relaxo values significantly.

The efficacy and toxicity of combined radiochemotherapy for locally advanced squamous cell carcinomas of the cervical oesophagus was evaluated retrospectively. Induction chemotherapy consisted of three courses of 5-fluorouracil (5-FU), leucovorin, etoposide and cisplatin (FLEP) or two courses weekly six times of 5-FU and leucovorin combined with biweekly cisplatin. This induction regimen was followed by high-dose external beam radiotherapy up to 60-66 Gy and concurrent chemotherapy with cisplatin and etoposide. Median follow-up of the recruited 17 patients was 37 months (13-73 months). Long-term survival was 24% at 2 and 3 years. The probabilities of locoregional tumour recurrences and distant metastases as sites of first relapse were 67 and 39% at 2 years. Acute and late toxicity of this schedule was moderate. The protocol offers a definitive chance of long-term survival for patients with locally advanced carcinomas of the cervical oesophagus, but local in-field recurrences remain the predominant risk after treatment. Intensification of the regimen seems possible because no dose-limiting late toxicities were observed.

The effect of fractionated irradiation on the oxygenation status of experimental tumours was investigated using polarographic assessment of the pO2 distribution. Since an improvement in tumour oxygenation could simply be the result of tumour shrinkage, a comparison of pO2 readings of untreated size-matched control tumours was performed. Irradiation was carried out using 6 fractions of 6 Gy applied within 11 days. A comparison of polarographic pO2 data with size-matched untreated tumours revealed a significant improvement in oxygenation after the irradiation. The median pO2 was 0.9+/-0.1 mm Hg for unirradiated tumours at a volume of 180 mm3, while the corresponding data for irradiated tumours of comparable size were 2.3+/-0.5 mm Hg on day 21 and 4.8+/-0.9 mm Hg on day 28 after start of irradiation. From these results it can be concluded that the improvement of oxygenation after fractionated irradiation is not solely the result of a reduced tumour volume.

Background and Purpose: This was an investigation to study the effect of giving carbogen and nicotinamide (CON) on pO2 and the radiation response of human xenografted tumours., Materials and Methods: The human xenografts were two sarcomas (ENE2 and ES3) and a glioblastoma (HTZ17). Nicotinamide (500 mg/ kg, i.p.) was administered 60 min before PO2 measurements and irradiation, while carbogen was given for 5 min before and during these treatments. Tumour pO2 was measured with an Eppendorf electrode and radiation response was assessed by local tumour control following irradiation with 10 daily fractions., Results: All three xenografts were found to be poorly oxygenated (about 80% of all pO2 values were < or =2.5 mmHg). CON treatment improved the oxygenation status in all three tumours such that 65, 52 and 71% of the pO2 values were < or =2.5 mmHg in ENE2, ES3 and HTZ17, respectively. However, only in ES3 was this decrease significant. The TCD50 doses for all tumours were around 52-54 Gy. No significant improvement was seen with CON in ENE2 (TCD50 = 48 Gy) and HTZ17 (TCD50 = 56 Gy), but for the ES3 xenograft a significant decrease to 42 Gy was found., Conclusions: The three tumours used in this study appeared to show the same level of hypoxia as measured both by pO2 and radiation response. However, only one tumour showed a significant improvement after CON treatment, suggesting that not all hypoxic human tumours might benefit from this type of therapy.

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.

Purpose: Split dose experiments were carried out with two 2 Gy fractions per day at intervals ranging from 0.5 to 24 h, in order to investigate both the time to complete repair and the detailed kinetics of repair of sublethal damage in the cervical spine of rats., Materials and Methods: Male rats of the WAG/Rij strain were irradiated at 2 Gy/min with 18 MV photons to a length of 18 mm of cervical spinal cord. Four hundred twenty-three rats were irradiated without top-up doses to investigate whether repair was complete by 24 h or whether any slow repair or proliferation occurred up to 50 days after irradiation. Three hundred seventy-nine rats were also irradiated in split dose (2 Gy + delta t + 2 Gy each day) experiments, with intervals of 0.5, 1, 2, 4, 8 and 24 h. The split dose irradiations were followed by a single top-up dose of 15 Gy (producing about half the total damage)., Results: Repair was complete by 24 h as the ED50 values were the same at 1, 11 and 50 day intervals for two large fractions, and for 10 fractions in 10 or 50 days. A mono-exponential component of repair of T1/2 = 0.25 (95% CI 0.16-0.48) h was determined by direct analysis using all the data and T1/2 = 0.37 (0.28-0.53) h for the split 2 Gy doses with top-up only. A bi-exponential analysis did not fit better. The presence of a second component was demonstrated graphically, with T1/2 of about 6.5 h but with a wide confidence interval from near 0 to 13 h. However, the 24 h ED50 was significantly different from all ED50s except the 8 h value. Considering all data together, an upper limit of about 7 h could be placed on any long component, or else repair could not be complete by 24 h., Discussion and Conclusions: Two components of repair (0.7 and 3.8 h) have been reported by Ang et al. (Ang, K.K., Jiang, G.L., Guttenberger, R., Thames, H.D., Stephens, L.C., Smith, C.D. and Feng, Y. Impact of spinal cord repair kinetics on the practice of altered fractionation schedules. Radiother. Oncol. 25: 287-294, 1992) in the spinal cord of Sprague-Dawley rats. Two components have also been reported by others more recently. The present results could, with its graphical interpretation, agree in principle, but with a shorter fast component and a longer slow component. A slow component of 5.5 h was reported by Ruifrok et al. (Ruifrok, A.C.C., Kleiboer, B.J. and van der Kogel, A.J. Fractionation sensitivity of rat cervical spinal cord during radiation retreatment. Radiother. Oncol. 25: 295-300, 1992) in a related strain of WAG/Rij rats. The possible presence of a slower component than Ang et al.'s 3.8 h might help to explain the four myelopathies observed in the pilot studies for the CHART clinical trial. The presence of the definite fast component (< 0.5 h) could have important consequences when pulsed brachytherapy is used to replace continuous low dose rate irradiation.

Purpose: Postoperative radiation therapy adds significantly to disease control and survival of patients with ependymoma. However, much controversy exists about the radiation treatment policy. We report the long-term results of a cohort of 56 patients with primary intracranial and spinal ependymomas. Special effort has been taken to define prognostic indicators as a basis for future treatment strategies., Patients and Methods: Between November 1963 and May 1995, 56 patients with histological proven ependymoma were referred to our clinic for further treatment following surgery. Thirty patients had a high grading tumor and 26 had low grade tumors. Seventeen patients had supratentorial tumors and 24 had infratentorial tumors. Fifteen patients suffered from localized spinal tumors., Results: The mean survival time for all patients was 77 months. Five- and 10-year survival probabilities were 60 and 51%, respectively. The mean progression free survival (PFS) probability for all patients was 67 months with corresponding 5- and 10-year PFS probabilities of 53 and 39%, respectively. On univariate analysis initial performance status, age and tumor grade were significant for survival probability. Concerning PFS radiation dose was significant with improved survival with doses > 45 Gy. On multivariate analysis, tumor grade and initial performance status proved to be the only independent prognostic factors., Conclusions: Tumor grade, age, initial performance status and radiation dose are significant factors for the clinical course of patients and have to be taken into account for the urgently needed prospective trials.

Seven spindle cell sarcomas, 5 poorly differentiated ones and 2 moderately well differentiated ones, were established on nude mice and long term passaging was done. Sarcoma strains were analysed electron microscopically in an attempt to get further insight in spindle cell sarcoma differentiation pathways. Ultrastructurally, the tumours were classified as malignant peripheral nerve sheath tumour (3/7), leiomyosarcoma (2/7), rhabdomyosarcoma (1/7), and spindle cell sarcoma not otherwise classifiable (1/7). Undifferentiated tumour cells including fibroblastoid ones predominated in most xenografts, whereas cells harbouring cytoplasmic specificities tended to be few in number. Nevertheless, divergent differentiations exhibiting unusual double or triple patterns could be documented ultrastructurally in 12/30 xenografts with juxtaposed myomatous as well as nerve sheath-like cells and, in addition, histiocytoid (MFH-like) elements in 3 of the xenografts. Moreover, sarcoma strains alternated fine structural constellations in the course of passaging, whereby different phenotypes, myomatous, nerve sheath-like, unspecific, or mixed ones, succeeded one another. These findings pursue recent immunohistochemical data on multidirectional sarcoma differentiation by means of electron microscopy. They, furthermore, fit well into the concept of multipotential stem cells as progenitors in mesenchymal differentiation and suggest microenvironment to play a modifying role in the expression of cell differentiation.

Background and Purpose: The aim of this study was to evaluate the biological equivalence of continuous low dose rate (LDR) irradiations to multifractionated high dose rate (HDR) regimes. The applicability of the LQ model was analysed for fraction sizes and dose rates relevant for the clinic., Material and Methods: Investigations were performed in mouse lip mucosa. HDR fractions were given in an overall treatment time ranging from 10 h to 3.5 days. The dose rate effect was analysed in the range of 84 to 0.76 Gy/h. For an assessment of biological equivalence in comparison to LDR, HDR irradiations have been performed in the same overall treatment time as the corresponding LDR regimes., Results: Recovery leads to sparing of radiation damage as the dose rate is reduced from 84 to 0.76 Gy/h (20.0 versus 45.7 Gy ED50). No significant additional sparing from 0.9 to 0.76 Gy/h could be demonstrated (44.9 versus 45.7 Gy ED50). Even 30 HDR fractions in 24 h were not sufficient to match the effect of LDR over the same time period (38.2 versus 41.1 Gy ED50). The present data give evidence for a bi-exponential repair process in mouse lip mucosa (T1/2 fast 27 min, T1/2 slow 150 min). Repair is dominated by the faster component (> 80%)., Conclusions: LDR is the most efficient way to deliver radiation if recovery is to be maximised and the overall time kept as short as possible. When used with realistic parameters the LQ model is capable of providing quantitative guidelines in areas of clinical interest.

Background: The role of adjuvant external radiotherapy in the survival of patients with differentiated thyroid cancer (DTC) is controversial. To our knowledge, no attempt has been undertaken thus far to assess the impact of this therapy with respect to the papillary and follicular types of thyroid cancer as separate entities., Methods: Between 1979 and 1992, 238 patients with differentiated papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) with Stage pT4 have been treated and followed in our clinic. One hundred sixty-nine patients free of metastases at the final staging, which was performed after the second radioiodine therapy, were included in this study. The standard treatment comprised total thyroidectomy, ablative radioiodine therapy, and thyroid-stimulating hormone-suppressive therapy with levothyroxin. Ninety-nine patients free of disease after the final staging received additional external radiotherapy to the neck (with a dose of 50-60 Gy), whereas the remaining 70 patients were treated with the standard treatment protocol only. Distributions of age, sex, and follow-up time were comparable in both irradiated and nonirradiated groups. Multivariate analysis of the influence of age, sex, histologic subtype, and lymph node status as well as of external radiotherapy on the time to first locoregional and distant failure (LDF), and the time to locoregional recurrence (LR), was accomplished using Cox's proportional hazard model., Results: In patients with DTC, external radiotherapy was a predictive factor for improvement of both LR (P = 0.004) and locoregional and distant failure (P = 0.0003). When the time to first locoregional and distant failure was calculated separately for patients with PTC and FTC, there was a significant difference in the PTC group in favor of irradiated patients (P = 0.0001), whereas there was no effect of external radiotherapy in the FTC group (P = 0.38). Further analyses disclosed that this effect was significantly present only in patients with PTC and lymph node involvement (P = 0.002), whereas those without lymph node involvement did not benefit from an additional adjuvant radiotherapy (P = 0.27). Because none of the patients younger than age 40 years died due to the disease nor had progressive disease during follow-up, we reassessed our results in patients older than age 40 years. The effect of external radiotherapy could be confirmed in this subgroup of patients (P = 0.0009) and in the subgroup of lymph node positive patients older than age 40 years with invasive PTC (P = 0.01)., Conclusions: In addition to total thyroidectomy, treatment with radioiodine, and TSH-suppressive therapy with thyroid hormone, adjuvant external radiotherapy improves the recurrence-free survival in patients older than age 40 years with invasive PTC and lymph node involvement.

Six human soft-tissue sarcoma and 14 glioma cell lines, exhibiting considerable differences in radioresponsiveness and histological grade of differentiation of the parental tumour, were examined with respect to apoptosis development after irradiation with 60Co gamma-rays. After test doses of 6 and 25 Gy, significant changes characteristic of apoptosis occurring within 6 to 30 hr were exhibited by only 2 differentiated sarcoma cell lines, EL7 and ESS2. The characteristic internucleosomal fragmentation of DNA was detected as early as 6 hr after exposure of subconfluent monolayer cultures to 6 Gy. It was limited to cells that had detached from the culture plate, whereas adherent cells showed random degradation of DNA, namely after higher doses (25Gy) or longer incubation times (30 hr). As assessed by fluorescence microscopy of unfixed cultures stained with Hoechst 33342 and propidium iodide, the proportion of cells showing apoptotic bodies in non-irradiated controls was < 0.1% and 0.3% for EL7 and ESS2, respectively. The dose-response relationship for apoptosis was determined at 9 hr post-irradiation. After 2 Gy, the percentage of apoptotic cells was elevated to 3.4% in EL7 and 4.5% in ESS2 cultures. Saturation was obtained above 6 Gy, with 8.4% apoptosis in EL7 and 15% in ESS2 after 25 Gy. Taken together, rapid ionizing-radiation-induced apoptosis seems to be limited to a subgroup of sarcomas and is unlikely to occur in gliomas.

Purpose: Current concepts to optimize the therapeutic gain of radiotherapy by hyperfractionation assume that human tumors are less sensitive to fractionation than late reacting normal tissues. The aim of this study was to investigate the extent of the intercell line heterogeneity of fractionation sensitivity of a wide variety of human tumor cell lines in a three-dimensional model system under fully oxic conditions using schedules with one to eight fractions. Biological characteristics of the tumors that correlate with fractionation sensitivity should be identified., Methods and Materials: A total of 21 cell lines from human tumors maintained as multicellular spheroids consisting of 1000-1500 cells were given fractionated irradiation within a total treatment time of maximally 50 h. Complete dose-spheroid control curves were determined for each fractionation scheme. The spheroid control data were adequately described by the linear quadratic model assuming Poisson statistics. In addition, the induction of a G2 block by a fractionated test dose of seven 3 Gy fractions given at 6-h intervals was determined in spheroid cells using flow cytometry of propidium bromide stained cell nuclei., Results: The fractionation sensitivities of human tumor cells in multicellular spheroids could be characterized by alpha/beta values, ranging from 2.8-37 Gy in dependence on the cell line. The log normally distributed alpha/beta values were positively correlated with the percentage increase in G2/M phase after the fractionated test dose compared to the controls (r = 0.72, p < 0.01), and were associated with the degree of tumor differentiation (p = 0.01, ANOVA F-test). No significant correlation between the log (alpha/beta) values and the surviving fractions at 2 Gy (SF2) or the total doses with 2 Gy per fraction necessary to control 50% of the spheroids (SCD50) was observed. Despite the intercell line variability of the alpha/beta values, the SCD50 values of the different cell lines, given with one and eight fractions or one fraction and 2 Gy per fraction, were closely associated (Spearman rank correlation coefficients: r = 0.89 or r = 0.90, p < 0.0001)., Conclusion: Human tumor cell lines showed a marked heterogeneity in the fractionation sensitivity when irradiated as multicellular spheroids and assayed in situ using the spheroid control end point. Therefore, the therapeutic gain of altered fractionation also depends on those biological characteristics of each individual tumor that affects its fractionation sensitivity. Parameters that correlate with fractionation sensitivity of the tumor lines in the spheroid system were identified as grade of tumor differentiation and percentage increase in G2/M cells at the end of an eight-fraction schedule.

Purpose: To evaluate the feasibility and effectiveness of a concurrent radio-chemotherapy regimen for locally advanced carcinomas of the pharynx and floor of the mouth., Patients and Methods: Since January 1990, 97 patients with locally advanced carcinomas of the naso-, oro-, hypopharynx and the oral cavity in UICC stages III and IV were treated according to an accelerated hyperfractionated radiotherapy schedule with concurrent chemotherapy. The primary tumor and positive lymph nodes received a total dose of 72 Gy in 6 weeks. In the first 3 weeks, large fields were irradiated 5 times per week with 2 Gy per fraction. Thereafter, treatment was accelerated, giving 2 daily fractions of 1.4 Gy with minimal intervals of 6 hours. Target volumes were reduced after 49.6 and 59.4 Gy, excluding clinically uninvolved lymph node regions of low and high risk. On day 1, 350 mg/m2 5-FU and 50 mg/m2 folinic acid were given as intravenous bolus followed by continuous infusion of 350 mg/m2 5-FU and 100 mg/m2 folinic acid, days 1 to 5. 10 mg/m2 mitomycin C was given on day 5 and 36 of the treatment. Salvage surgery was offered for residual disease 5 to 6 weeks after the end of radiotherapy., Patient Characteristics: 70 male, 27 female; age: 27 to 81 years; T2/T3/T4: 7/30/60; N0/N1/N2/N3: 20/18/53/6; nasopharynx/oropharynx/hypopharynx/oral cavity: 16/33/36/12. Median follow-up is 26 months., Results: Overall survival and recurrence-free survival at 2 years were, Results: Overall survival and recurrence-free survival at 2 years were 68 +/- 5% and 74 +/- 5%. Multivariate analysis revealed a significant influence of the geometric mean neck node diameter or the N-stage on loco-regional control and survival. T-stage, tumor volume, or tumor localisation did not become significant. Acute toxicity of this schedule was acceptable but required optimised supportive care. Treatment related grade 4+ late toxicity of mucosa, soft tissue and bone were observed with a cumulative frequency of 13% at 2 years. Two patients died during a phase of severe leuko- or thrombocytopenia., Conclusion: This phase I to II trial shows favourable results using an intensified treatment radio-chemotherapy protocol. A phase III study is now planned, comparing this regime with an accelerated hyperfractionated radio-therapy alone to an increased total dose of 77.6 Gy.

Oxygen tension distributions (pO2) were measured in 10 patients with recurrent soft tissue sarcoma (n = 4), recurrent rectal cancer (n = 2), recurrent breast cancer (n = 3) and recurrent neck nodes (n = 1) using computerized pO2 histography. Measurements were performed pretherapeutically and 24 hours after the first cytotoxic hyperthermic treatment. In one patient an increase of the mean pO2 value was evident after hyperthermia. The other 9 patients showed a significant decrease in the mean pO2 values after hyperthermia. Pooled pO2 distributions of measurements before and after hyperthermia differ statistically significant (p < 0.01). The median pO2 from 1248 measurements before hyperthermia is 18.9 mmHg, whereas the median pO2 from 1263 measurements after hyperthermia is 9.4 mmHg.

Purpose: Experimental in vivo radiotherapy frequently aims at the imitation of clinically applied fractionation schedules. However, the reliability of the anesthetic procedure and limited access to the treatment machines in clinical departments are major factors complicating the practical realisation of the experiment. Therefore, a reliable and time saving system for irradiations of xenografted tumors has been developed, which allows repeated irradiations, even in relatively short intervals available for experimental irradiations., Material and Methods: The system presented here consists of an acrylic distributor for an anesthetic gas mixture employing enflurane (Ethrane) in the center of the set-up. Ten mice are positioned radially around the midpoint of the set-up so that they can be irradiated simultaneously. The xenotransplanted tumors growing on the right hind leg of mice are placed in a predefined position, which was found to be of advantage in order to position the tumors for fractionated treatments in identical setting. Tumor-bearing mice are irradiated with 15 MeV photons generated by a linear accelerator at a dose rate of 2.5 Gy/min. One of the significant feature of the setup is the ability to irradiate in acute hypoxia which is obtained by use of an integrated tourniquet. The dose modifying effects of different gases can be investigated by simply using them as carrier for the enflurane., Results: With the use of the set-up several different experiments were performed so far. At most ten fractions were given, one fraction per day. Even after these repeated treatment the loss of animals due to narcosis was less than 2%. The dose variation within the treatment field was found to be less than 4% as measured with TLD dosimetry. The remaining body of the mice is shielded effectively from the direct beam as the whole body dose of mice is 8% of the total tumor absorbed dose. The efficacy of the tourniquet technique for acute hypoxic irradiations was illustrated with the use of 99mTc-labelled albumin showing a complete stop of blood flow in the clamped leg. The steep dose-response curve obtained for single dose irradiation of a neurogenic sarcoma is based on the physical and experimental precision which can be reached with the technique suggested here., Conclusion: Due to the high dose rate and the possibility to irradiate ten animals simultaneously the set-up introduced here is greatly time saving. The versatile applicability makes the new set-up a valuable tool for tumor radiobiology.

In previous experiments an anaesthetic gas mixture of enflurane (Ethrane, Abbott, Belgium) and oxygen has been used in our department to position mice for local irradiation. The development of a new immobilization method allowed the investigation of possible dose modifying effects of enflurane with different gases as carrier on the radiation response of mouse lip mucosa. The effect of different immobilization procedures on single dose and fractionated irradiations was examined. The experiments were compared on the basis of the dose associated with 50% incidence of lower lip desquamation (ED50 +/- 95% CI). When mice were breathing air the ED50 value following single dose irradiation was 20.0 (19.6 to 20.5) Gy. For mice receiving an anaesthetic gas mixture of enflurane and oxygen the ED50 was decreased significantly to 17.5 (17.2 to 17.8) Gy, indicating a sensitizing effect of the anaesthetic mixture by a factor of 1.14. The impact of different experimental set-ups on the fractionation sensitivity has been assessed. In order to estimate alpha/beta ratios in different treatment conditions two and ten fraction experiments were performed, additionally to the single dose irradiations. Dose modification factors were 1.09 for two fractions and 0.97 for the ten fraction experiment. This varying dose modification leads to a pronounced shift in alpha/beta ratios (estimated by "direct analysis" and graphically illustrated with a Fe-plot). For air breathing animals an alpha/beta ratio of 16.4 (14.5 to 18.9) Gy was estimated by direct analysis, whereas for the enflurane/oxygen anaesthesia 8.7 (7.3 to 10.2) Gy were calculated. Both these data sets were adequately described with the linear-quadratic formalism, as was shown with Tucker's analysis. The sensitizing effect of oxygen alone in single dose irradiations (DMF: 1.07) suggests moderate physiological hypoxia in mouse lip mucosa. The present data emphasize the effect of different immobilization procedures on the estimation of alpha/beta ratios, especially when large fraction sizes are involved. Data from experiments involving large fraction sizes should be avoided in the estimation of repair parameters. Further experimental work has to be carried out to elucidate the possible dose modifying effects of anaesthetic agents in clinical practice, e.g. for infants and for patients undergoing intraoperative radiotherapy.

The present study investigated the effect of fractionated low dose-rate (FLDR) treatments in mouse lip mucosa, a typically early reacting tissue. The relation between dose-rate and fractionation effect has been assessed with various interfraction intervals and dose-rates. A fixed overall treatment time of 10 h has been used for the present continuous and fractionated irradiation experiments with corresponding dose-rates of 3.1-84 Gy/h. Sophisticated mathematical models are now available to estimate repair parameters from data derived with different fraction numbers, fraction sizes and dose-rates. These formulas, allowing the calculations of isoeffect relationships are based on the incomplete repair model and assume that repair can operationally be described by a monoexponential function. A further assumption of these models is that repair of sublethal damage follows the same kinetics during irradiation and between fractions. The present FLDR experiments with small interfraction spacing were performed to investigate the validity of these assumptions and consequently the applicability of the models. In addition, it has been assessed whether the experimental approach of investigating repair kinetics as such [high dose-rate (HDR) split-course vs. continuous low dose-rate (CLDR) or FLDR] influences the estimation of these parameters, as has been suggested from the analysis of in vitro studies. Using the mucosal desquamation endpoint, virtually identical repair parameters have however been estimated with different approaches (alpha/beta = 14.1-18.2 Gy, T1/2 = 28-37 min). The available isoeffect models seem to be applicable to the present experimental data and might after further experimental tests also involving late reacting tissues, be a useful tool for clinical isoeffect calculations.