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Purpose: To assess the robustness of scanned ion beam treatment plans against the interfraction internal target motion and evaluate the limits of validity of target-based isocenter realignment for prostate cancer radiation therapy. Methods and Materials: For 12 prostate patients, scanned beam carbon ion treatment plans were prepared using 2 lateral opposed beams and the raster scanning technique with different clinical target volume (CTV) to planning target volume (PTV) margins (2-10 mm). Internal target motion of 2-15 mm in anteroposterior (AP), superoinferior (SI), and left-to-right (LR) directions was simulated by displacing the CTV contours with respect to the computed tomography data. The plans were recalculated with and without target-based isocenter realignment and the CTV coverage was assessed. Results: For CTV shifts within the applied planning margin, the CI-98% is greater than 98.0%, both with and without isocenter realignment. Without realignment, because of the sharp lateral gradients, the CI-98% shows rapid fall as soon as the target shift exceeds the applied planning margin for all displacement directions. With isocenter realignment, the coverage improves notably for shifts in AP and SI directions and the CI-98% is restored to >95.0% for plans optimized with a 2-mm margin, >97% with a 3-mm margin, and >98%more » with larger margins. For large corrections, predominately in AP direction, cold spots in the CTV may occur. Their magnitude is dependent on the patients' individual anatomies. Conclusions: Within the physiological limits of internal prostate movement, target-based isocenter realignment results in improved CTV coverage for shifts in AP and SI directions exceeding the applied planning margin. Assuming optimal patient setup reproducibility (eg, immobilization, setup error correction, patient preparation protocols), hence negligible interfraction bone and soft-tissue variations, changes in traversed densities resulting from target-based realignment applied with a reduced planning margin do not induce significant dose deterioration in most of the cases.« less

Objective Primary diffuse leptomeningeal gliomatosis (PDLG) is a rare neoplasm with a short survival time of a few months. there is currently no standardized therapeutic approach for PDLG. Materials and methods We report on a 53-year-old male patient who presented with epileptic seizures, gait disturbance, paraparesis and sensory deficits in the dermatomes T8-10. Results Magnetic resonance imaging (MRI) revealing numerous spinal and cranial gadolinium-enhancing nodules in the meninges and histopathology led us to diagnose primary diffuse leptomeningeal gliomatosis with WHO grade III astrocytic cells. Consecutively, the patient underwent craniospinal radiotherapy (30 Gy) and 11 sequential cycles of temozolomide. This regimen led to partial tumor regression. Thirteen months later, spinal MRI revealed tumor progression. Second-line chemotherapy with 5 cycles of irinotecan and bevacizumab did not prevent further clinical deterioration. The patient died twenty-two months after diagnosis, being the longest survival time described thus far with respect to PDLG consisting of astrocytic tumor cells. Conclusions Radiochemotherapy including temozolomide, as established standard therapy for brain malignant astrocytomas, might be valid as a basic therapeutic strategy for this PDLG subtype.

Each medical intervention must be performed respecting Health Protection directives, with special attention to Quality Assurance (QA) and Quality Control (QC). This is the basis of safe and reliable treatments. BNCT must apply QA programs as required for performance and safety in (conventional) radiotherapy facilities, including regular testing of performance characteristics (QC). Furthermore, the well-established Quality Management (QM) system of the nuclear reactor used has to be followed. Organization of these complex QM procedures is offered by the international standard ISO 9001:2008.

In boron neutron capture therapy, the absorbed dose from the (10)B(n,alpha)(7)Li reaction depends on the (10)B concentration and (10)B distribution in the irradiated volume. Thus compounds used in BNCT should have tumor-specific uptake and low accumulation in normal tissues. This study compares in a mouse model the (10)B uptake in different organs as delivered by l-para-boronophenylalanine (BPA, 700 mg/kg body weight, i.p.) and/or sodium mercaptoundecahydro-closo-dodecaborate (BSH, 200 mg/kg body weight, i.p). After BSH injection, the (10)B concentration was high in kidneys (20 +/- 12 microg/g) and liver (20 +/- 12 microg/g) but was low in brain (1.0 +/- 0.8 microg/g) and muscle (1.9 +/- 1.2 microg/g). After BPA injection, the (10)B concentration was high in kidneys (38 +/- 25 microg/g) and spleen (17 +/- 8 microg/g) but low in brain (5 +/- 3 microg/g). After combined BPA and BSH injection, the effect on the absolute (10)B concentration was additive in all organs. The ratio of the (10)B concentrations in tissues and blood differed significantly for the two compounds depending on the compound combination, which implies a different uptake profile for normal organs.

It has been reported that the level of cytogenetic damage in human peripheral blood lymphocytes (PBL) is higher following irradiation at 37 degrees C than at 0-4 degrees C. The mechanisms of this cytogenetic temperature effect are not fully known. The aim of our study was to check whether the effect was related to the indirect or direct action of radiation.PBL were kept at 37 degrees C and 0 degree C for 20 min and exposed to 2 Gy of X-rays. In some experiments PBL were isolated and 0.5 M dimethyl sulfoxide (DMSO) was added for 5 min before exposure. PBL were also irradiated at 37 degrees C and 0 degree C with 1 Gy of 6 MeV neutrons. Micronuclei were scored as the endpoint. Following exposure to X-rays the level of initial DNA damage was also measured by the alkaline and neutral comet assay.The frequency of micronuclei in cells exposed at 37 degrees C to X-rays or neutrons was higher than that after exposure at 0 degree C. No effect of temperature was seen when PBL were exposed to X-rays in the presence of DMSO. No effect of temperature was observed on the level of DNA damage measured with the alkaline or neutral comet assay.The results of experiments with DMSO indicate that the temperature effect is due to the indirect action of radiation, i.e., via reactive oxygen species. However, this is not supported by the results with neutrons and the comet assay. Possible reasons for the discrepancies are discussed.

Boron neutron capture therapy (BNCT) provides highly targeted delivery of radiation through the limited spatial distribution of its effects. This translational research/phase I clinical trial investigates whether BNCT might be developed as a treatment option for squamous cell carcinoma of head and neck (SCCHN) relying upon preferential uptake of the two compounds, sodium mercaptoundecahydro-closo-dodecaborate (BSH) or L-para-boronophenylalanine (BPA) in the tumour. Before planned tumour resection, three patients received BSH and three patients received BPA. The (10)B-concentration in tissues and blood was measured with prompt gamma ray spectroscopy. Adverse effects from compounds did not occur. After BPA infusion the (10)B-concentration ratio of tumour/blood was 4.0 +/- 1.7. (10)B-concentration ratios of tumour/normal tissue were 1.3 +/- 0.5 for skin, 2.1 +/- 1.2 for muscle and 1.4 +/- 0.01 for mucosa. After BSH infusion the (10)B-concentration ratio of tumour/blood was 1.2 +/- 0.4. (10)B-concentration ratios of tumour/normal tissue were 3.6 +/- 0.6 for muscle, 2.5 +/- 1.0 for lymph nodes, 1.4 +/- 0.5 for skin and 1.0 +/- 0.3 for mucosa. BPA and BSH deliver (10)B to SCCHN to an extent that might allow effective BNCT treatment. Mucosa and skin are the most relevant organs at risk.

Graves' disease (GD) is an autoimmune disease that typically affects the thyroid gland. Thirty to sixty percent of patients also suffer from orbital inflammation. Retrobulbar radiotherapy for Graves' orbitopathy (GO) has been used for decades, though there is no direct evidence for the influence of dose and fractionation schedules on various signs and symptoms. Indeed, optimal fractionation schedules and recommended total irradiation doses are still a matter of discussion. Our aim was to investigate treatment efficacy of retrobulbar irradiation for GO at different total absorbed doses and fractionation schedules.A retrospective evaluation of 129 patients who were examined before, as well as 6-8 months after irradiation with different treatment schedules at eight radiotherapeutic departments. Total absorbed doses were 12, 16, or 20 Gy. All patients were additionally treated with systemic application of corticosteroids. Treatment efficacy was evaluated through assessment of proptosis, horizontal and vertical ocular motility and of clinical activity (CAS). Overall group and individual responses were evaluated. Treatment response was defined as inactivation of GO, reduction of proptosis by at least 2 mm, improvement of motility byor = 8 degrees or unchanged normal parameters.Prior to irradiation, neither age, disease duration, gender distribution, smoking behavior or serologic parameters, nor clinical activity or severity stages varied significantly between groups. Neither did outcome measures, except proptosis, differ significantly. Retrobulbar irradiation led to inactivity of GO in approximately 80% of patients, with no significant group difference. After irradiation with 16 and 20 Gy, vertical motility improved in a significantly higher percentage of patients than after irradiation with 12 Gy. Median improvement of vertical motility in responding patients was excellent in all groups (15 degrees at 12 Gy, 10 degrees at 16 Gy, 10 degrees at 20 Gy). Horizontal motility did not change significantly.If the aim of retrobulbar irradiation is primarily to reduce soft-tissue signs, lower doses are sufficient. If a patient also suffers from dysmotility, doses exceeding 12 Gy may be more effective.

Single liver metastases of colorectal cancer can be cured by surgery; disseminated liver metastases are incurable. A research group in Pavia, Italy, used BNCT as an experimental method to irradiate in curative intention the explanted liver of patients suffering from disseminated hepatic metastases. The situation in Pavia, where a reactor with a specially adapted thermal column and the hospital are close by, is unique. For the purpose of the present study, it was necessary to investigate how the Pavia experience can be repeated with transplantation centers located at distance from a reactor. Some basic investigations of the logistics of such a procedure are reported.

The cure or long-term survival of hilar cholangiocarcinoma patients can only be achieved after complete tumor resection. Many patients though suffer from unresectable hilar cholangiocarcinoma, and palliative treatment is therefore the only therapeutic option. In cases of unresectable bile duct cancer, intraoperative radiotherapy (IORT) is an additional option during surgery. The aim of this study was to compare the efficacy of IORT to surgery alone in patients with unresectable hilar cholangiocarcinoma.Palliative IORT (group 1) was performed on 9 patients (4 female/5 male); surgery alone (group 2) was performed in a case-matched group of 9 patients (4 female, 5 male) with unresectable hilar cholangiocarcinoma. The mean ages were 52.9 years (group 1) and 57.2 years (group 2). The two groups had comparable local tumor extension and stages of tumor disease according to UICC 6th edition. Group 1 was also compared to all 36 patients (n=36) suffering from unresectable cholangiocarcinoma treated without IORT (Group 3).The survival of patients after IORT was significantly improved compared to surgery alone in this study. The median survival time was 23.3 months (group 1) versus 9.4 months (group 2) and 5.7 month (group 3). The one year and two year actuarial survival rates are: 56% and 42% (group 1), 33% and 0% (group 2), 25% and 8% (group 3).Palliative surgery including IORT is safe for patients with unresectable hilar cholangiocarcinoma. The benefit shown by this investigation is a significant improvement of survival time after application of IORT in the palliative situation. A prospective study with randomization is needed to confirm these first results in a larger cohort.

For the treatment of conjunctival lymphoma in the early stages, external beam radiotherapy offers a curative approach. Such treatment requires the use of highly conformed small radiation beams. The beam size is so small that even advanced treatment planning systems have difficulties in calculating dose distributions. One possible approach for optimizing the treatment technique and later performing treatment planning is by means of full Monte Carlo (MC) simulations. In this paper, we compare experimental absorbed dose profiles obtained with a collimator used at the University Hospital Essen, with MC simulations done with the general-purpose radiation transport code PENELOPE. The collimator is also simulated with the hybrid MC code electron Monte Carlo (eMC) implemented in the commercial treatment planning system Eclipse (Varian). The results obtained with PENELOPE have a maximum difference with experimental data of 2.3%, whereas the eMC code differs systematically from the experimental data about 7% in the penumbra tails. We also show that PENELOPE simulations are able to obtain absorbed dose maps with an equivalent statistical uncertainty to the one found with eMC in similar CPU times.

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.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.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.In combination with CC, there was no trend towards an improved efficacy of HART in comparison with CFRT.

The exact intracellular localization and distribution of molecules and elements becomes increasingly important for the development of targeted therapies and contrast agents. We show that laser postionization secondary neutral mass spectrometry (laser-SNMS) is well suited to localize particular elements and small molecules with subcellular spatial resolution applying the technique exemplary to Boron Neutron Capture Therapy (BNCT). We showed in a murine sarcoma that the drugs used for clinical BNCT, namely l-para-boronophenylalanine (700 mg/kg body weight i.p.) and sodium mercaptoundecahydro-closo-dodecaborate (200 mg/kg body weight i.p.), transport the therapeutic agent 10B into the cytoplasm and into the nucleus itself, the most sensitive area of the cell. Sodium mercaptoundecahydro-closo-dodecaborate distributes 10B homogeneously and l-para-boronophenylalanine heterogeneously. When combining laser-SNMS with prompt γ-ray analysis as a screening technique, strategies for BNCT can be elaborated to develop new drugs or to improve the use of existing drugs on scientifically based evidence. The study shows the power of laser-SNMS in the early stages of drug development, also outside BNCT. [Mol Cancer Ther 2008;7(7):1763–71]

In 2001, at the TRIGA reactor of the University of Pavia (Italy), a patient suffering from diffuse liver metastases from an adenocarcinoma of the sigmoid was successfully treated by boron neutron capture therapy (BNCT). The procedure involved boron infusion prior to hepatectomy, irradiation of the explanted liver at the thermal column of the reactor, and subsequent reimplantation. A complete response was observed. This encouraging outcome stimulated the Essen/Petten BNCT group to investigate whether such an extracorporal irradiation could be performed at the BNCT irradiation facility at the HFR Petten (The Netherlands), which has very different irradiation characteristics than the Pavia facility. A computational study has been carried out. A rotating PMMA container with a liver, surrounded by PMMA and graphite, is simulated using the Monte Carlo code MCNP. Due to the rotation and neutron moderation of the PMMA container, the initial epithermal neutron beam provides a nearly homogeneous thermal neutron field in the liver. The main conditions for treatment as reported from the Pavia experiment, i.e. a thermal neutron fluence of 4 x 10(12) +/- 20% cm(-2), can be closely met at the HFR in an acceptable time, which, depending on the defined conditions, is between 140 and 180 min.

PURPOSE: To assess the occurrence and development of cerebral radiologic changes (cerebral atrophy and white matter lesions) in patients treated with boron neutron capture therapy (BNCT) for primary supratentorial glioblastoma multiforme within the European Organization for Research and Treatment of Cancer (EORTC) trial 11961.METHODS AND MATERIALS: Magnetic resonance imaging (MRI) scans were performed before and after surgery and at 1 week and 2, 4.5, 6, 9, 12, 15, and 18 months after BNCT. For the current study, MRI scans of all assessable patients were analyzed, with emphasis on cerebral atrophy and white matter abnormalities.RESULTS: Twenty-six patients had been treated with BNCT according to the EORTC trial 11961, of whom 24 were assessable for the current study. The development of possible BNCT-related cerebral changes was observed in 12 patients (50%), 10 of whom had cerebral atrophy (42%) and 10 white matter changes (42%) after a median interval of 7.5 and 4.5 months, respectively.CONCLUSION: In this study, cerebral radiologic changes appeared in 50% of patients within the first year after BNCT. Although a clear correlation between the BNCT dose and the development of cerebral changes could not be demonstrated, a relationship between the occurrence of these radiologic abnormalities and BNCT seems likely.

Defining the parameters influencing the biological reaction due to absorbed dose is a continuous topic of research. The main goal of radiobiological research is to translate the measurable dose of ionizing radiation to a quantitative expression of biological effect. Mathematical models based on different biological approaches (e.g., skin reaction, cell culture) provide some estimations that are often misleading and, to some extent, dangerous. Conventional radiotherapy is the simplest case because the primary radiation and secondary radiation are both low linear energy transfer (LET) radiation and have about the same relative biological effectiveness (RBE). Nevertheless, for this one-dose-component case, the dose-effect curves are not linear. In fact, the total absorbed dose and the absorbed dose per fraction as well as the time schedule of the fractionation scheme influence the biological effects. Mathematical models such as the linear-quadratic model can only approximate biological effects. With regard to biological effects, fast neutron therapy is more complex than conventional radiotherapy. Fast neutron beams are always contaminated by gamma rays. As a consequence, biological effects are due to two components, a high-LET component (neutrons) and a low-LET component (photons). A straight transfer of knowledge from conventional radiotherapy to fast neutron therapy is, therefore, not possible: RBE depends on the delivered dose and several other parameters. For dose reporting, the European protocol for fast neutron dosimetry recommends that the total absorbed dose with gamma-ray absorbed dose in brackets is stated. However, boron neutron capture therapy (BNCT) is an even more complex case, because the total absorbed dose is due to four dose components with different LET and RBE. In addition, the terminology and units used by the different BNCT groups is confusing: absorbed dose and weighted dose are both to be stated in grays and are never "photon equivalent." The ICRU/IAEA made proposals, which should be followed by all BNCT groups, to report always the four absorbed dose components, boron dose DB, proton dose Dp, gamma-ray dose Dgamma, and neutron dose Dn, as well as the sum DT of all components, as total absorbed dose, together with the total weighted dose Dw (to be used only for internal purposes, indicating the used weighting factors) at all points of interest and the treatment conditions.

Since October 1997, a clinical trial of Boron Neutron Capture Therapy (BNCT) for glioblastoma patients has been in progress at the High Flux Reactor, Petten, the Netherlands. The trial is a European Organisation for Research and Treatment of Cancer (EORTC) protocol (#11 961) and, as such, must be conducted following the highest quality management and procedures, according to good clinical practice and also other internationally accepted codes. The complexity of BNCT involves not only strict international procedures, but also a variety of techniques to measure the different aspects of the irradiation involved when treating the patient. Applications include: free beam measurements using packets of activation foils; in-phantom measurements for beam calibration using ionisation chambers, pn-diodes and activation foils; monitoring of the irradiation beam during patient treatment using fission chambers and GM-counters; boron in blood measurements using prompt gamma ray spectroscopy; radiation protection of the patient and staff using portable radiation dosimeters and personal dosimeters; and in vivo measurements of the boron in the patient using a prompt gamma ray telescope. The procedures and applications of such techniques are presented here, with particular emphasis on the importance of the quality assurance/quality control procedures and its reporting.

SBRT for Lung Metastases: A Pooled Analysis of 651 Patients and 868 Lesions of the German Working Group Stereotactic Radiotherapy F. Sterzing, J. Streblow, K. Scherer, S. Adebahr, N. Adratschke, J. Boda-Heggemann, O. Blanck, M. Duma, I. Ernst, G. Gademann, U. Ganswindt, C. Henkenberens, D. Imhoff, H. Kahl, F. Lohaus, G. Lubinski-de Lange, A. Maertin, C. Petersen, A. Wittig, and M. Guckenberger; University Hospital, Heidelberg, Germany, University Hospital, Freiburg, Germany, University Hospital, Zurich, Switzerland, University Hospital, Mannheim, Germany, University Clinic, Luebeck, Germany, Klinikum rechts der Isar, TU Munchen, Munich, Germany, University of Muenster, Muenster, Germany, University Hospital, Magdeburg, Germany, University of Munich, Munich, Germany, MH, Hannover, Germany, University Hospital, Frankfurt, Germany, Hospital Augsburg, Augsburg, Germany, University Hospital, Dresden, Germany, Radiation Oncology, Paderborn, Germany, University Hospital, Jena, Germany, University Hospital, Hamburg, Germany, University Hospital, Marburg, Germany, University Hospital, Wuerzburg, Germany

Purpose of this work was to implement Monte Carlo (MC) dose computation in realistic patient geometries with raster-scanning, the most advanced ion beam delivery technique, combining magnetic beam deflection with energy variation. FLUKA, a Monte Carlo package well-established in particle therapy applications, was extended to simulate raster-scanning delivery with clinical data, unavailable as built-in feature. A new complex beam source, compatible with FLUKA public programming interface, was implemented in Fortran to model the specific properties of raster-scanning, i.e. delivery by means of multiple spot sources with variable spatial distributions, energies and numbers of particles. The source was plugged into the MC engine through the user hook system provided by FLUKA. Additionally, routines were provided to populate the beam source with treatment plan data, stored as DICOM RTPlan or TRiP98's RST format, enabling MC recomputation of clinical plans. Finally, facilities were integrated to read computerised tomography (CT) data into FLUKA. The tool was used to recompute two representative carbon ion treatment plans, a skull base and a prostate case, prepared with analytical dose calculation (TRiP98). Selected, clinically relevant issues influencing the dose distributions were investigated: (1) presence of positioning errors, (2) influence of fiducial markers and (3) variations in pencil beam width. Notable differences in modelling of these challenging situations were observed between the analytical and Monte Carlo results. In conclusion, a tool was developed, to support particle therapy research and treatment, when high precision MC calculations are required, e.g. in presence of severe density heterogeneities or in quality assurance procedures.

The compound p-(dihydroxy)-boronophenylalanine (BPA) is currently being evaluated as a boron-carrier for BNCT in clinical trials.1,2 Knowledge of the uptake and efflux mechanisms of BPA in and from tumor cells might allow a specific modification of those processes aiming at a higher intracellular boron concentration.

We compared the amount of radiation-induced DNA damage and the extent of DNA repair in human melanoma cells (MeWo) using the 'comet assay' after neutron, boron neutron capture and X-irradiation. Using a colony-forming assay it was shown earlier that lethal effects in tumour cells treated with fast neutrons may be increased by the neutron capture reaction 10B(n, alpha)7Li. The effectiveness of boron neutron capture in killing tumour cells depends on the number of 10B atoms delivered to the tumour, the subcellular distribution of 10B and the thermal neutron fluence at the side of the tumour. Using the 'comet assay' the DNA damage of fast neutrons (mean energy 5.8 MeV) was shown to be significantly greater than for the same absorbed dose of X-rays. The presence of 600 ppm 10B (boric acid H5 10BO3) in the cell medium during irradiation with d(14) + Be neutrons in a phantom enhances the DNA damage by 20% compared with neutron irradiation alone. After DNA damage induction by neutrons and neutron capture of boron, the DNA repair capacity of the MeWo cells is significantly reduced in comparison with X-irradiation resulting in proportionally more residual DNA damage after 180 min of repair time.

Aim To study the dose-response of stage I non-small-cell lung cancer (NSCLC) in terms of long-term local tumor control (LC) after conventional and hypofractionated photon radiotherapy, modeled with the linear-quadratic (LQ) and linear-quadratic-linear (LQ-L) approaches and to estimate the clinical α/β ratio within the LQ frame. Material and methods We identified studies of curative radiotherapy as single treatment through MedLine search reporting 3-year LC as primary outcome of interest. Logistic models coupled with the biologically effective dose (BED) at isocenter and PTV edge according to both the LQ and LQ-L models with α/β = 10 Gy were fitted. Additionally, α/β was estimated from direct LQ fits. Results Thirty one studies were included reporting outcome of 2319 patients. The LQ-L fit yielded a significant value of 11.0 ± 5.2 Gy for the dose threshold (Dt) for BED10 at the isocenter. The LQ and LQ-L fits did not differ substantially. Concerning the estimation of α/β, the value obtained from the direct LQ fit for the complete fractionation range was 3.9 [68 % CI: 2.2–9.0] Gy (p > 0.05). Conclusion Both LQ and LQ-L fits can model local tumor control after conventionally and hypofractionated irradiation and are robust methods for predicting clinical effects. The observed dose-effect for local control in NSCLC is weaker at high doses due to data dispersion. For BED10 values of 100–150 Gy in ≥3 fractions, the differences in isoeffects predicted by both models can be neglected. Electronic supplementary material The online version of this article (doi:10.1186/s13014-016-0643-5) contains supplementary material, which is available to authorized users.