A domestic porcine model for studying the effects of radiation on head and neck cancers.

BACKGROUND: Radiation therapy (RT) of the head and neck region is often accompanied by serious side effects. Research in this area is needed to improve treatment outcomes and ameliorate therapy tolerance. Laboratory rodents are barely matching today's clinical standards in RT research. Yet domestic swine (Sus scrofa domestica) have previously proved suitable for various advanced tests in clinical research and training. We therefore investigated whether S. scrofa domestica is also appropriate for irradiation of the mandible. STUDY DESIGN: A common scheme for irradiation treatment of S. scrofa domestica mandibles in a split-mouth design was acquired by applying computed tomography (CT) scanning under sedation. Basing on close anatomic resemblance, a standard treatment plan comprising 2 opposed irradiation fields could be accomplished. RESULTS: RT was carried out in a clinical environment with 2 × 9 Gy. The resulting operating procedure facilitated complication-free sedation, transport, positioning, CT scanning, and effective irradiation. CONCLUSION: Based on common standards applied for RT in humans, domestic pigs can be employed to progress RT clinical research. Due to their human-like anatomy, physiology, size, and weight, the swine model is expedient for advancing experimental RT of the head and neck area.

BMP-2 immobilized on nanocrystalline diamond-coated titanium screws; demonstration of osteoinductive properties in irradiated bone.

BACKGROUND: Irradiation results in impaired bone healing. Thus, osteosynthesis procedures are afflicted with increased failure rates. To improve osseointegration bone morphogenetic protein-2 (BMP-2) immobilized on nanocrystalline diamond (NCD)-coated implant surfaces might be 1 solution. METHODS: By 4 weeks after irradiation of pig's mandible with a dose of 60 Gy a fracture was accomplished. Osteosynthesis was performed either with titanium osteosynthesis screws or NCD-coated screws with immobilized BMP-2. Nonirradiated animals served as control. After 1, 2, 4, and 8 weeks screws were evaluated histologically. Bone biopsies were gained to extract mesenchymal stem or precursor cells (MSCs). RESULTS: MSCs after irradiation demonstrated a behavior comparable to that of unirradiated cells. Consequently, immobilized BMP-2 resulted in an initial increased bone contact ratio (p = .014) but demonstrated no sustainable effect compared with osseointegration in nonirradiated bone (p = .08). CONCLUSION: Immobilized BMP-2 demonstrates an osteoinductive effect in irradiated bone. MSCs as effector cells possess protective mechanisms to overcome the destructive effect of irradiation.

Mesenchymal stem cells show radioresistance in vivo.

Irradiation impacts on the viability and differentiation capacity of tissue-borne mesenchymal stem cells (MSC), which play a pivotal role in bone regeneration. As a consequence of radiotherapy, bones may develop osteoradionecrosis. When irradiating human bone-derived MSC in vitro with increasing doses, the cells' self-renewal capabilities were greatly reduced. Mitotically stalled cells were still capable of differentiating into osteoblasts and pre-adipocytes. As a large animal model comparable to the clinical situation, pig mandibles were subjected to fractionized radiation of 2 χ 9 Gy within 1 week. This treatment mimics that of a standardized clinical treatment regimen of head and neck cancer patients irradiated 30 χ 2 Gy. In the pig model, fractures which had been irradiated, showed delayed osseous healing. When isolating MSC at different time points post-irradiation, no significant changes regarding proliferation capacity and osteogenic differentiation potential became apparent. Therefore, pig mandibles were irradiated with a single dose of either 9 or 18 Gy in vivo, and MSC were isolated immediately afterwards. No significant differences between the untreated and 9 Gy irradiated bone with respect to proliferation and osteogenic differentiation were unveiled. Yet, cells isolated from 18 Gy irradiated specimens exhibited a reduced osteogenic differentiation capacity, and during the first 2 weeks proliferation rates were greatly diminished. Thereafter, cells recovered and showed normal proliferation behaviour. These findings imply that MSC can effectively cope with irradiation up to high doses in vivo. This finding should thus be implemented in future therapeutic concepts to protect regenerating tissue from radiation consequences.

[Updated strategies in Small Cell Lung Cancer post ASCO 2007]. / Das kleinzellige Bronchialkarzinom - neue Entwicklungen nach ASCO 2007.

Small Cell Lung Cancer (SCLC) is associated with intensive nicotine consumption and characterized by a very aggressive growth rate. Furthermore, metastases often appear very early. At the annual meeting of the "American Society of Clinical Oncology" (ASCO) 2007, recent issues which will influence the daily clinical practice were presented. New chemotherapy combinations such as carboplatin/irinotecan or pemetrexed as well as targeted therapies e.g. bevacizumab in combination with chemotherapy could extend our therapeutic options. A genetic polymorphism, which influences the pharmacokinetic of irinotecan, turned out to be one reason for the different outcome of an irinotecan/cisplatin therapy in a Japanese and Northern American population. In the field of radiotherapy, a phase III study showed for the first time a significant benefit in overall survival by prophylactic cranial radiation in the setting of extensive disease.

[Small cell lung cancer]. / Das kleinzellige Bronchialkarzinom.

With about 20% of all lung cancers small cell lung cancer (SCLC) represents a major subset of this entity. Although therapeutic improvements did not receive as much attention as in non small cell lung cancer (NSCLC), many small steps of clinical progress have been achieved within the last 20 years. An optimal treatment should be based on an interdisciplinary treatment plan. The standard treatment in localized stages represents combined radiation and chemotherapy. Cisplatin and etoposide are in this concern considered as a gold standard. 3D-planned conformal radiotherapy should start as early as possible and should be applied concomitantly to chemotherapy and in certain cases even in a hyperfractionated treatment protocol. In very early stages surgical resection could be an option in selected cases. In advanced stages a platinum-based doublet offers high response rates. As already established in limited disease prophylactic cranial irradiation is now also indicated in extensive disease in case of any tumor remission. In the second line treatment and in patients with reduced performance status topotecan is recommended. Similar as in NSCLC pemetrexed might become an alternative treatment option in the second line setting. In the field of new targeted therapies bevacizumab achieved the most promising results. The present review highlights historical milestones and up-to-date trends in radiotherapy, chemotherapy and surgery. Furthermore, the role of experimental strategies and the management of certain special clinical situations are discussed.

Comparative treatment planning on localized prostate carcinoma conformal photon- versus proton-based radiotherapy.

PURPOSE: To assess the potential benefit of proton-beam therapy in comparison to 3-D conformal photon therapy and photon- based intensity-modulated radiotherapy (IMRT) in prostate carcinoma for various stages of disease. MATERIAL AND METHODS: In five patients a 3-D conformal proton-based (two lateral beams) irradiation technique was compared with 3-D conformal photon-beam radiotherapy (four-field box) and IMRT (seven beams). For each patient different target volumes (CTVs) were defined according to early, intermediate and advanced stages of disease: CTV I consisted of the prostate gland, CTV II encompassed prostate and basis of seminal vesicles, and CTV III the prostate and seminal vesicles. Corresponding planning target volumes PTV I-III were defined by uniformly adding a margin of 5 mm to CTV I-III. Dose-volume histograms (DVHs) were analyzed for the different PTVs and various organs at risk (OARs), i.e., rectal wall, bladder, both femoral heads. In addition, maximum and mean doses were derived for the various structures and irradiated non-target tissue volumes were compared for PTV I-III and the different irradiation techniques. Finally, dose conformity and target dose homogeneity were assessed. RESULTS: With photon- and proton-based radiotherapy techniques similar dose distributions were determined for PTV I-III: mean and maximum PTV dose values were between 99-104% and 102-107% of the normalized total doses (70 Gy), respectively. Conformity indices varied from 1.4 to 1.5 for the photon techniques, whereas for proton-beam radiotherapy values ranged from 1.1 to 1.4. Both the 3-D conformal and the IMRT photon treatment technique resulted in increased mean doses (approximately 40-80%) for OARs when compared to protons. With both photon techniques non-target tissue volumes were irradiated to higher doses (mean dose difference > or = 70%) compared to proton-beam radiotherapy. Differences occurred mainly at the low and medium dose levels, whereas in high dose levels similar values were obtained. In comparison to conformal 3-D treatments IMRT reduced doses to OARs in the medium dose range, especially for the rectal wall. CONCLUSION: IMRT enabled dose reductions to OARs in the medium dose range compared to 3-D conformal radiotherapy. A rather simple two-field proton-based treatment technique further reduced doses to OARs compared to photon-beam radiotherapy. The advantageous dose distribution of proton-beam therapy for prostate cancer may result in reduced side effects, which needs to be confirmed in clinical studies.

Reproducibility of patient positioning for fractionated extracranial stereotactic radiotherapy using a double-vacuum technique.

BACKGROUND AND PURPOSE: Precise reproducible patient positioning is a prerequisite for conformal fractionated radiotherapy. A fixation system based on double-vacuum technology is presented which can be used for conventional as well as hypofractionated stereotactic extracranial radiotherapy. MATERIAL AND METHODS: To form the actual vacuum mattress, the patient is pressed into the mattress with a vacuum foil which can also be used for daily repositioning and fixation. A stereotactic frame can be positioned over the region of interest on an indexed base plate. Repositioning accuracy was determined by comparing daily, pretreatment, orthogonal portal images to the respective digitally reconstructed radiographs (DRRs) in ten patients with abdominal and pelvic lesions receiving extracranial fractionated (stereotactic) radiotherapy. The three-dimensional (3-D) vectors and 95% confidence intervals (CI) were calculated from the respective deviations in the three axes. Time required for initial mold production and daily repositioning was also determined. RESULTS: The mean 3-D repositioning error (187 fractions) was 2.5 +/- 1.1 mm. The largest single deviation (10 mm) was observed in a patient treated in prone position. Mold production took an average of 15 min (10-30 min). Repositioning times are not necessarily longer than using no positioning aid at all. CONCLUSION: The presented fixation system allows reliable, flexible and efficient patient positioning for extracranial stereotactic radiotherapy.

Treatment planning comparison of conventional, 3D conformal, and intensity-modulated photon (IMRT) and proton therapy for paranasal sinus carcinoma.

PURPOSE: To determine the potential improvements in patients with paranasal sinus carcinoma by comparing proton and intensity-modulated radiotherapy (IMRT) with conventional and conformal photon treatment planning techniques. METHODS AND MATERIALS: In 5 patients, comparative treatment planning was performed by comparing proton plans and related conventional, conformal, and IMRT photon plans. The evaluations analyzed dose-volume histogram findings of the target volumes and organs at risk (OARs, i.e., pituitary gland, optical pathway structures, brain, nontarget tissue). RESULTS: The mean and maximal doses, dose inhomogeneities, and conformity indexes for the planning target volumes were comparable for all techniques. Photon plans resulted in greater volumes of irradiated nontarget tissues at the 10-70% dose level compared with the corresponding proton plans. The volumes thereby increased by a factor of 1.3-3.1 for conventional, 1.1-3.8 for conformal, and 1.1-3.7 for IMRT. Compared with conventional techniques, conformal and IMRT photon treatment planning options similarly reduced the mean dose to the OARs. The use of protons further reduced the mean dose to the OARs by up to 65% and 62% compared with the conformal and IMRT technique, respectively. CONCLUSION: Compared with conventional treatment techniques, conformal RT and IMRT similarly enabled dose reductions to the OARs. Additional improvements were obtained using proton-based treatment planning modalities.

Epidemiological aspects of hadron therapy: a prospective nationwide study of the Austrian project MedAustron and the Austrian Society of Radiooncology (OEGRO).

BACKGROUND: The planned MedAustron hadron therapy facility is designed to compare proton and carbon ion beam therapy under the same technical conditions. For the calculation of the number of potential patients for hadron therapy so far, only epidemiological estimations on cancer incidence are available without inclusion of the percentage of patients routinely referred to conventional radiotherapy. MATERIALS AND METHODS: Nationwide prospective survey to collect disease and treatment related data on patients receiving conventional radiotherapy at all 12 treatment facilities. Epidemiological cancer incidence (Statistic Austria 1999) were correlated with the number of patients receiving conventional radiotherapy. Based on published clinical and experimental results on proton and carbon ion therapy, a calculation of patient's subgroups suitable for hadron therapy was performed at five European University hospitals involved in the HICAT, CNAO, ETOILE and MEDAustron project. Using the mean values of the University specific percentages per tumour site, the number of potential patients was estimated. RESULTS: In Austria, a total of 3783 patients started radiotherapy during the study period of 3 months resulting in an approximated number of 15132 patients per year. The number of potential patients was estimated to 2044 per year, representing 5.6% of all newly diagnosed cancer patients and 13.5% of all irradiated cancer patients. CONCLUSION: There is a clear place for a hadron therapy facility in Austria, based on pattern of care in radiotherapy, cancer incidence and indications.

The med AUSTRON/OGRO patterns of care study on radiotherapy indications in Austria.

PURPOSE: In Austria a national survey was conducted by Med AUSTRON/Osterreichische Gesellschaft for Radio--Onkologie, Radiobiologie und Medizinische Radiophysik (OGRO) in order to estimate the indications, patient numbers and radiotherapy treatment planning procedures and performances at all Austrian radiotherapy institutes. Results were correlated with incidence rates (Austrian cancer registry) to determine patterns of radiotherapy practice in Austria. MATERIAL AND METHODS: At 12 radiotherapy departments of Austria data of all patients receiving irradiation within a 3 months (2002/2003) period were assessed. On the basis of a questionnaire number of treated patients, indications, and parameters of disease (stage, histology) and treatment modalities were evaluated. Results were analysed with regard to different tumour groups, according to academic and non academic hospitals, and correlated with epidemiological data on cancer incidence. RESULTS: In total, 3783 patients were registered within this period. According to the different tumour entities percentages of patients receiving radiotherapy within initial treatment varied from 3% to 90 % (e.g. brain tumours: 77%, breast cancer: 90%, prostate cancer: 35%). The most frequent indications to radiotherapy per radiotherapy department were breast cancer (range 22%-35%; mean 26%), urological tumours (range 6%-27%; mean 12%) and bone metastases (mean 10%, range 3%-17%). CONCLUSION: In Austria breast cancer, urological tumours and bone metastases are representing the most common indications to radiotherapy. Among the different departments variations in indications to radiotherapy were observed. Our study is the first evaluation of radiotherapeutic management in Austria.

Light ion facility projects in Europe: methodological aspects for the calculation of the treatment cost per protocol.

In the framework of the European Network for Research in Light Ion Hadron Therapy (ENLIGHT), the health economics group develops a methodology for assessing important investment and operating costs of this innovative treatment against its expected benefits. The main task is to estimate the cost per treated patient. The cost analysis is restricted to the therapeutic phase from the hospital point of view. An original methodology for cost assessment per treatment protocol is developed based on standard costs. Costs related to direct medical activity are based on the production process analysis, whereas indirect and non direct medical costs are allocated to each protocol using relevant cost-drivers. The resulting cost model will take into account the specificities of each therapeutic protocol as well as the particularities of each of the European projects.