Effects of radiation exposure are observed in virtually all normal tissues. Early reactions occur primarily in turnover tissues (e.g., bone marrow, epidermis, mucosae of the gastrointestinal tract), where proliferative impairment results in progressive hypoplasia and eventually complete loss of functional cells, after a tissue dependent but dose independent latent time. These early radiation reponses are regularly preceded and accompanied by vascular and inflammatory reactions. In contrast, late reactions are based on combined parenchymal, vascular, and connective tissue changes; very late effects are dominated by vascular sequelae. In most instances, a significant involvement of the immune system can also be demonstrated for chronic radiation sequelae, and a contribution of neural changes is discussed. The orchestrated response of all tissue components results in loss of function within the exposed volume. Importantly, latent times of late effects are inversely dependent on dose. Hence modern, highly conformal treatment techniques with relatively low and inhomogeneous doses in the organs at risk (OAR) require very long follow-up intervals with a precise assessment and documentation of the complication endpoints for characterisation of the treatment-induced morbidity profile. Consequential late effects (CLEs) develop through interactions between early and late effects in the same organ; they follow the radiobiological principles of the early reactions. The clinical manifestation of radiation responses is defined by several parameters, summarized as the "R's of radiobiology". First, each individual symptom or endpoint of radiation-induced morbidity follows an individual dose-effect relationship (intrinsic 'R'adiosensitivity), in many instances related to the dose within specific subvolumes of the individual OAR, rather than e.g., the mean organ dose. The biological effectiveness of a certain (total) dose is modulated by exposure conditions: Changes in dose fractionation protocols ('R'recovery) predominantly impact on late responding tissues, while overall treatment time ('R'epopulation) predominantly affects early (and consequential late) reactions. Consequences of partial organ exposure (i'R'adiated volume") are related to tissue architecture. In mainly 'tubular' or 'serial' organs (e.g., gastrointestinal tract, but also vasculature), local exposure affects function in downstream compartments. In contrast, in predominantly 'parallel' organs, such as liver or lungs, only exposure of a significant (organ-dependent) fraction of the total volume results in clinical consequences. However, all organs in fact are composed of tubular and serial components. Translational studies into damage processing (molecular 'R'adiopathology), starting immediately after the onset of radiation exposure, but proceeding for long and very long time intervals even at subclinical levels, intra-and intercellular signals and signalling pathways may be identified that are relevant or even specific for the clinical manifestation of morbidity endpoints. These can serve as a basis to identify (early) biomarkers of the individual risk for specific tissue reactions and endpoints, and also for establishment of strategies to prevent/mitigate tissue effects after exposure.

The adequate and sustainable handling of risk presents a plethora of challenges. This is especially true for research and practice in medicine, where proper risk management demands transparency and an awareness of the risks, challenges, and opportunities involved.

The purpose of this work was to prove the validity of the mean lung dose (MLD), widely used in clinical practice to estimate the lung toxicity of a treatment plan, by reevaluating experimental data from mini pigs.

In modern radiation oncology, tolerance dose-constraints for organs at risk (OAR) must be considered for treatment planning, but particularly in order to design clinical studies. Tolerance dose tables, however, only address one aspect of the therapeutic ratio of any clinical study, i.e., the limitation of adverse events, but not the desired potential improvement in the tumor effect of a novel treatment strategy. A sensible application of "tolerance doses" in a clinical situation requires consideration of various critical aspects addressed here: definition of tolerance dose, specification of an endpoint/symptom, consideration of radiation quality and irradiation protocol, exposed volume and dose distribution, and patient-related factors of radiosensitivity. The currently most comprehensive estimates of OAR radiation tolerance are in the QUANTEC compilations (2010). However, these tolerance dose values must only be regarded as a rough orientation and cannot answer the relevant question for the patients, i.e., if the study can achieve a therapeutic advantage; this can obviously be answered only by the final scientific analysis of the study results. Despite all limitations, the design of clinical studies should currently refer to the QUANTEC values for appreciation of the risk of complications, if needed supplemented by one's own data or further information from the literature. The implementation of a consensus on the safety interests of the patients and on an application and approval process committed to progress in medicine, with transparent quality-assuring requirements with regard to the structural safeguarding of the study activities, plays a central role in clinical research in radiation oncology.

ObjectiveThe goal of this study was to investigate the local tumor blood supply parameters relative tumor blood volume (rTBV) and transfer coefficient (Ktrans) measurable with dynamic contrast enhanced computed tomography (DCE-CT) in patients with non-small-cell lung cancer (NSCLC) scheduled for radiation therapy (RT).Materials and methodsrTBV and Ktrans were measured before RT in 31 patients with clinically inoperable NSCLC (Stages I–III), which received (n=19) or did not receive (n=12) induction chemotherapy (IChT). Possible links between rTBV and Ktrans and time-to-progression (TTP), overall survival (OS) and maximum standardized uptake value (SUVmax) from fluorodeoxyglucose positron emission tomography as well as histology were analyzed.ResultsNSCLC showed a wide range of rTBV and Ktrans values as estimated by DCE-CT (6.4±0.6ml/100ml and 18.2±1.5ml/100ml/min correspondingly). A significant difference in rTBV values in patients with IChT (4.6±0.6ml/100ml) and without IChT (7.5±0.9ml/100ml; p=0.023), depending on the number of cycles of the IChT and the clinical stage was found. A negative correlation between rTBV and TTP was revealed only in RT patients up-staged by FDG-PET/CT from stage III to stage IV (n=7, r=−0.96, p=0.0006). An inverse correlation between Ktrans and TTP (n=24, r=−0.53, p=0.008) was observed in all RT patients. No relevant correlation was detected between rTBV, Ktrans and SUVmax or histologic subtypes and grading.ConclusionsTumor blood supply parameters derived from DCE-CT are useful to characterize tumor vascularization before radiotherapy in patients with NSCLC and data on outcome prediction are supplemented.

Purpose: The aim of the study was to record patients' symptoms of anxiety, depression and post-traumatic stress, as well as their subjective experience of illness, with different forms of radiotherapy and for different indications. The question is to be answered of whether more invasive techniques such as stereotactic radiotherapy involve greater stress or whether the psychological stress instead tends to be caused by the underlying disorder itself. Patients and Methods: Questionnaires were given to 240 patients after conventional radiotherapy for a malignant underlying disorder, to 80 with a benign disorder, and to 67 patients following stereotactic radiotherapy. The German version of the Hospital Anxiety and Depression Scale (HADS-D) was used to measure anxiety and depression; the Post-Traumatic Symptom Scale (PTSS-10) was used to measure symptoms related to post-traumatic stress disorder (PTSD), and there were questions about patients' subjective experience of radiotherapy. Results: 28% of all patients scored in the pathologic or borderline anxiety range; 26% were in the pathologic or borderline depression range. 22% of patients were above the diagnostic cutoff for the PTSS-10. No differences were evident between the three groups in terms of anxiety and stress-related symptoms. Women were significantly (p = 0.001) more severely affected by symptoms of PTSD and anxiety than men. No gender differences could be proven in terms of depression. In the HADS-D, patients with a benign underlying disorder had significantly (p < 0.05) lower depression values than the two other groups studied. Conclusion: Patients who had undergone stereotactic radiotherapy did not demonstrate higher values for anxiety, depression or PTS symptoms than patients treated with conventional radiotherapy. From the results submitted here it cannot be assumed that this form of treatment leads to an increased incidence of traumatic stress or even post-traumatic stress disorder (PTSD). All in all, it is the type of underlying disorder (malignant/benign), which affects the extent of psychological stress experienced by patients following radiotherapy.

Purpose: The aim of the study was to record patients’ symptoms of anxiety, depression and post-traumatic stress, as well as their subjective experience of illness, with different forms of radiotherapy and for different indications. The question is to be answered of whether more invasive techniques such as stereotactic radiotherapy involve greater stress or whether the psychological stress instead tends to be caused by the underlying disorder itself. Patients and Methods: Questionnaires were given to 240 patients after conventional radiotherapy for a malignant underlying disorder, to 80 with a benign disorder, and to 67 patients following stereotactic radiotherapy. The German version of the Hospital Anxiety and Depression Scale (HADS-D) was used to measure anxiety and depression; the Post-Traumatic Symptom Scale (PTSS-10) was used to measure symptoms related to post-traumatic stress disorder (PTSD), and there were questions about patients’ subjective experience of radiotherapy. Results: 28% of all patients scored in the pathologic or borderline anxiety range; 26% were in the pathologic or borderline depression range. 22% of patients were above the diagnostic cutoff for the PTSS-10. No differences were evident between the three groups in terms of anxiety and stress-related symptoms. Women were significantly (p = 0.001) more severely affected by symptoms of PTSD and anxiety than men. No gender differences could be proven in terms of depression. In the HADS-D, patients with a benign underlying disorder had significantly (p < 0.05) lower depression values than the two other groups studied. Conclusion: Patients who had undergone stereotactic radiotherapy did not demonstrate higher values for anxiety, depression or PTS symptoms than patients treated with conventional radiotherapy. From the results submitted here it cannot be assumed that this form of treatment leads to an increased incidence of traumatic stress or even post-traumatic stress disorder (PTSD). All in all, it is the type of underlying disorder (malignant/benign), which affects the extent of psychological stress experienced by patients following radiotherapy.

Purpose and Approach: To report a case of morphea (Localized scleroderma) in a patient following breast cancer therapy and to summarize the current literature.Results and Conclusion: The occurrence of morphea is an unexpected late effect (approximately 1 year after the end of radiation therapy) which occurs frequently in the irradiated breast in women with breast-conserving therapy. The pathogenesis is unclear. The main differential diagnoses are recurrence of carcinoma and a radiogenic subcutaneous fibrosis (in most cases, the final diagnosis can only be made by means of a biopsy). Diagnosis and therapy must be performed in cooperation between dermatologist and radiooncologist.

Background and purpose Local failure is a significant issue following radiotherapy (RT) for patients with non-small cell lung cancer (NSCLC). The aim of this study was to find out whether FDG-PET/CT is capable to predict tumor relapse location in patients with NSCLC, in particular to determine high risk tumors' subvolumes responsible for local failure. Material and methods Ten patients with locoregional relapse of NSCLC underwent FDG-PET/CT before, during, and in the 4–12 months following curative chemoradiotherapy (ChRT, 66 Gy) using a combined PET/CT scanner. Morphologic and metabolic tumor volumetry and an evaluation of FDG-uptake dynamics were performed. Results CT showed partial reduction of tumor volume after RT in all patients. PET-revealed partial in eight patients and complete metabolic response in two patients during RT. Six to nine months after RT, local failure was diagnosed in all patients with both methods. Tumor recurrences were localized mostly in the most active ones of pre-therapeutically metabolic regions of the primary tumor. Conclusions Local failure in NSCLC appears most common at the primary site and within the irradiated target volume with the highest FDG uptake. This observation may be useful for further optimization of radiotherapy of NSCLC, for example, by the application of additional radiation dose to subvolumes of primary tumors with higher FDG uptake.

Background and purpose: Loco-regional failure after radiotherapy with total doses of 60-70 Gy for non-small cell lung cancer (NSCLC) remains a major clinical problem. Escalation of radiation dose is often limited because of exceeding normal tissue constraints. The present study was designed to test the hypothesis that a reduction in disease volume during radiotherapy detected by FDG PET/CT would facilitate radiation dose escalation, whilst remaining within normal tissue constraints.Materials and methods: Ten patients with localised inoperable NSCLC were prospectively enrolled. Each received standard 3D-conformally planned radiotherapy to a dose of 66 Gy in 33 fractions over 6.5 weeks. FDG PET/CT imaging in the treatment position was performed prior to treatment and repeated following 50 or 60 Gy. CT and PET-delineated gross tumour volumes were generated and a composite created. A margin of 15 mm was added in all planes to form the planning target volume (PTV). Treatment planning was performed to compare two dose escalation strategies: 78 Gy delivered to the initial PTV with treatment in two phases (shrinking field), i.e., 66 Gy to the initial PTV with a 12 Gy-boost to the PTV after 50/60 Gy. As an alternative planning approach the maximal dose without exceeding normal tissue constraints was evaluated for each patient (individualized dose prescription).Results: There was a median PTV reduction after 50/60 Gy of 20%. Delivering 78 Gy to the initial PTV could have been achieved in 4/10 patients. Of the remaining 6, delivering 78 Gy to the initial PTV would have exceeded normal tissue constraints and no benefit was seen when delivered in two phases. The results from the individualized dose prescription indicated a higher median maximal dose when treatment would be given in two phases compared to one phase resulting in a modest increase of calculated tumour control probability.Conclusions: Our data suggest that despite tumour shrinkage determined by subsequent FDG PET/CT during treatment the tested adaptive targeting strategy would result only in a modest improvement in the context of dose escalation. Further studies on the optimal use of FDG PET/CT and other approaches for dose escalation in loco-regionally advanced NSCLC are warranted. (C) 2008 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 88 (2008) 335-341.