Since 2006 a clinical phase I/II study is carried out treating prostate cancer patients with a combination of Cion irradiation and IMRT (C-ion treatment at GSI, IMRT in Heidelberg). In parallel to this therapy, a study investigating chromosome aberrations in blood lymphocytes of prostate cancer patients is performed, as described in [1]. Chromosome aberrations in blood lymphocytes are widely used in biological dosimetry as they represent a sensitive marker for ionizing radiation. Since they are unavoidably exposed to radiation during tumor treatment, this study makes it possible to investigate in vivo the cytogenetic effects of C-ion radiation and to compare with conventional tumor irradiation. Patients are irradiated with C-ion boost (6x3GyE) and IMRT (30x2Gy) or solely with IMRT (38x2Gy). Blood samples are drawn from each patient before, during, at the end of and one year after therapy. Lymphocytes are cultured according to standard techniques [2]. Chromosome spreads are prepared and slides are stained using Fluorescence-Plus-Giemsa staining (FPG) and multiplex fluorescence in situ hybridization (mFISH), respectively. To investigate the individual radiosensitivity, a blood sample from each patient before therapy is irradiated in vitro (3Gy X-rays). The results are compared to those of healthy donors (fig. 1). Slight differences in the aberration yield were observed, but no significantly increased radiosensitivity of one patient was found, nor an enhanced sensitivity of all patients compared to healthy donors.

This paper presents the BioShuttle platform as a delivery vehicle for transfer of contrast agents and genetic material into target cells, which can be followed by activation of the BioShuttle inside the target cell. Here, we present a transporter system and summarize the findings on transporter use in vivo and in vitro. The results here are limited to examples where cargoes (drugs, genetically active materials or contrast agents) are covalently associated with the transporter module. A further example, in which the cargo is non-covalently attached to the BioShuttle, is also discussed. Finally, attempts have been made to solve some of the issues surrounding the efficiency of transfer of therapeutic or diagnostic agents and their later activity in the cell.

Purpose: The aim of this study was to evaluate the effectiveness and toxicity of carbon ion radiotherapy in chordomas of the skull base.Methods and Materials: Between November 1998 and July 2005, a total of 96 patients with chordomas of the skull base have been treated with carbon ion radiation therapy (RT) using the raster scan technique at the Gesellschaft fur Schwerionenforschung (GSI) in Darmstadt, Germany. All patients had gross residual tumors. Median total dose was 60 CGE (range, 60-70 CGE) delivered in 20 fractions within 3 weeks. Local control and overall survival rates were calculated using the Kaplan-Meier method. Toxicity was assessed according to the Common Terminology Criteria (CTCAE v.3.0) and the Radiation Therapy Oncology Group (RTOG) / European Organization for Research and Treatment of Cancer EORTC) score.Results: Mean follow-up was 31 months (range, 3-91 months). Fifteen patients developed local recurrences after carbon ion RT. The actuarial local control rates were 80.6% and 70.0% at 3 and 5 years, respectively. Target doses in excess of 60 CGE and primary tumor status were associated with higher local control rates. Overall survival was 94.8% and 88.5% at 3 and 5 years, respectively. Late toxicity consisted of optic nerve neuropathy RTOG/EORTC Grade 3 in 4.1% of the patients and necrosis of a fat plomb in 1 patient. Minor temporal lobe injury (RTOG/EORTC Grade 1-2) occurred in 7 patients (7.2%).Conclusions: Carbon ion RT offers an effective treatment option for skull-base chordomas with acceptable toxicity. Doses in excess of 75 CGE with 2 CGE per fraction are likely to increase local control probability. (C) 2007 Elsevier Inc.

Background Pancreatic cancer is the fourth commonest cause of death from cancer in men and women. Advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor (EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR. Methods/design The PARC study is designed as an open, controlled, prospective, randomized phase II trial. Patients in study arm A will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine infusions weekly over 4 weeks. Patients in study arm B will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine weekly over 4 weeks and cetuximab infusions over 12 weeks. A total of 66 patients with locally advanced adenocarcinoma of the pancreas will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patient's enrolment. Discussion The primary objective of this study is to evaluate the feasibility and the toxicity profile of trimodal therapy in pancreatic adenocarcinoma with chemoradiation therapy with gemcitabine and intensity modulated radiation therapy (IMRT) and EGFR-targeted therapy using cetuximab and to compare between two different methods of cetuximab treatment schedules (concomitant versus concomitant and sequential cetuximab treatment). Secondary objectives are to determine the role and the mechanism of cetuximab in patient's chemoradiation regimen, the response rate, the potential of this combined modality treatment to concert locally advanced lesions to potentially resectable lesions, the time to progression interval and the quality of life.

Purpose: To investigate the feasibility of raster scanned heavy charged particle therapy in the treatment of prostate cancer (PCa,) with special regard to the influence of internal organ motion on the dose distribution.Methods and Materials: The CT data of 8 patients with PCa who underwent three-dimensional conformal radiotherapy (RT) were chosen. In addition to the routine treatment planning scan, three to five additional positioning control CT scans were performed. The organs at risk and the target volumes were defined on all CT scans. Primary and boost carbon ion plans were calculated to deliver 66 Gy to the clinical target volume/planning target volume, with an additional 10 Gy to the gross tumor volume (GTV). To estimate the influence of internal organ motion on plan quality, the dose was recalculated on the basis of the control CT scans. The comparative analysis was based on the dose-volume histogram-derived physical parameters.Results: The average 90% target coverage was 99.1% for the GTV. The maximal dose to the rectum was 71.8 Gy. The average rectal mean dose was 19 Gy. The volume of the rectum receiving 70 and 68 Gy was 0.1 and 0.3 cm(3). The average difference in the 90% coverage for the GTV on control CT cubes was 3.6%. The maximal rectal dose increased to 76.2 Gy. The deviation in the mean rectal dose was <1 Gy on average. The rectal volume receiving 70 and 68 Gy increased to 2.5 and 3.3 cm(3).Conclusion: The investigation demonstrated the feasibility of raster scanned carbon ions for PCa RT. Excellent coverage of the target volume and optimal sparing of the rectum were acquired. The combination of photon intensity-modulated RT and a carbon ion boost to the GTV is the most rational solution for the gain of clinical experience in heavy ion RT for PCa patients. (C) 2004 Elsevier Inc.

The GSI carbon ion radiotherapy facility established the first completely active beam shaping system for heavy ions, using energy variation on the synchrotron and pencil beam scanning. The introduction of an active beam shaping system for carbon ions has considerable impact on the design of the treatment planning system (TPS). The TPS has to account for the capability of the beam delivery and the biological modelling, which is needed to calculate the RBE for the resulting varying depth dose modulation. The TPS used in clinical routine with carbon ions is described and its use in treatment planning studies are outlined. A clinical trial with carbon ion therapy as primary therapy for chordoma and chondrosarcoma of the base of skull has been completed in 2001. Currently, carbon ion therapy as a boost treatment together with conventional conformal photon therapy or IMRT is under investigation in clinical trials for adenoid cystic carcinoma, chordoma and chondrosarcoma of the cervical spine and sacrococcygeal chordoma. Treatment planning studies comparing carbon ion therapy with IMRT, using optimization of combination therapy, and optimization of beam-line design have already been completed. Analysis of uncertainties in treatment planning has been started with the investigation of range uncertainties stemming from CT imaging. Uncertainties coming from the beam delivery play only a minor role. An attempt to asses the uncertainties introduced in treatment plans by the biological modelling, was done, using phantom verification of calculated cell survival levels. The clinical trials and planning studies are of special importance for the upcoming new clinical ion facility of the Heidelberg university hospital.

Carbon ion radiation therapy (RT) is available at the German Ion Research Center (GSI) in Darmstadt, Germany, since December 1997. Patient treatments within the pilot project are carried out by radiation oncologists of the University of Heidelberg in cooperation with the Department of Biophysics of GSI, the Division of Medical Physics of the German Cancer Research Center Heidelberg and the Research Center Rossendorf. Patients are treated within three beam time blocks of 20 days per year at the basic physics research center at GSI, the overall capacity per year being 45 to 50 patients. Main purpose of the pilot project was to investigate carbon ion radiation therapy for different tumor entities within clinical phase I/II trials. This manuscript updates the results of the clinical phase I/II trial of carbon ion RT in chordomas and low grade chondrosarcomas of the skull base and summarizes the current status of the ongoing phase I/II trial for extracranial chordomas and low grade chondrosarcomas.

Spinal chordomas cannot be treated with an effective dose using conventional radiation therapy (RT) without exceeding the tolerance dose of the spinal cord while ensuring sufficient target coverage at the same time. In this study we investigate the potential physical advantages of combined photon intensity-modulated radiation therapy (IMRT) and raster-scanned carbon ion RT over photon IMRT alone. For a representative patient we generated a carbon ion RT plan and a photon IMRT plan. Additionally, combined plans consisting of both carbon ions and photon IMRT were calculated using ratios of 20:40 GyE, 30:30 GyE and 40:20 GyE. The best target coverage was obtained using carbon ions alone. Using a combination of photon IMRT and carbon ions, the target coverage was better than with photon IMRT alone. Due to the applied dose constraints, the sparing of the spinal cord was comparable for all plans. Using carbon ions alone, the non-target tissue volume irradiated to at least 30 GyE/50.4 GyE was reduced by 72%/84% compared to photon IMRT alone. These advantages were evident even with combined techniques. The actually delivered dose distribution is expected to be more dependent on patient misalignment with carbon ions compared with photon IMRT. A combination of carbon ions and photon IMRT might be preferable in order to profit by the physical advantages of carbon ions while ensuring a safe treatment.

The implementation of computer-assisted three-dimensional radiotherapy treatment planning methods based on computed tomography together with sophisticated beam modeling with individual blocks and multi-leaf-collimators in the 90's enabled the creation of steep dose gradients between the target volume and surrounding radiosensitive normal tissue. For prostate cancer, a clear dose dependence between the treated radiation dose and the treatment success is proven, especially for patients with intermediate and unfavorable prognostic criteria. However, with conventional radiotherapy, rectum and urinary bladder are limiting the applicable dose. New technical methods allow a safe dose escalation without increasing of treatment-related toxicity. An improvement in terms of PSA remission and local control was yielded. This article presents the different established external beam and interstitial treatment techniques and their clinical results.

Purpose/Objective: The aim of this analysis is to evaluate the feasibility of inverse treatment planning and intensity modulated radiation therapy (IMRT) for head and neck cancer in daily clinical routine. A step and shoot IMRT approach was developed which allows the treatment of large target volumes without the need to use a split beam technique. By using the IMRT approach better protection of different organs at risk in the head and neck region may be achieved and an escalation of the dose in the tumor should be possible. We evaluated the feasibility of the treatment technique and the patient tolerance to the treatment. First clinical results are reported.Materials and Methods: Between 1999 and 2002, 48 patients with a carcinoma of the head and neck region were treated with curative intention. All patients were treated in a patient-specific Scotch-Cast mask. Patients who required treatment of the lymph node levels I–VI, were additionally positioned by a vacuum pillow in order to immobilize the upper part of the thorax. For inverse treatment planning, the software module KonRad was used which was integrated into the VIRTUOS planning system. Each treatment plan was verified using quantitative film dosimetry in a head and neck phantom. The step and shoot IMRT technique with a multileaf collimator integrated in a Primus (Siemens®) accelerator was used for treatment. For all target volumes the whole target including the lymph nodes were covered completely by the IMRT treatment.Results: The mean total dose for the target volumes of macroscopic disease ranged between 63.0 and 64.1Gy. The mean total dose of microscopic disease ranged between 55.2 and 60.1Gy. The mean percentage of planning target volume receiving <90% of the prescribed dose ranged between 3.0 and 11.5% . For the treatment, the median number of beams was seven (range: five to nine). The time to deliver the treatment ranged between 9 and 18min. The results of the verification revealed a mean deviation between measured and calculated absolute doses for the 48 patients of 0.1±1.4%. Including the phantom verification the IMRT treatment of the patients could be started approximately after five working days. The treatment was well tolerated by all patients. The 2-year actuarial overall survival was 92% and the 2-year actuarial local control rate was 93%. According to the Radiation Therapy Oncology Group (RTOG), no higher acute toxicity than Grade 3 was seen. Observation of the late effects revealed only one transient Grade 4 toxicity of the bone and only four patients had a xerostomia higher than Grade 1.Conclusion: The use of an inversely-planned and intensity-modulated step and shoot approach is feasible in clinical routine for head and neck tumors. Treatment could be applied as planned and no increased toxicity was found. Compared to other IMRT approaches for the head and neck region the used technique allows the treatment of the primary tumor and the lymph nodes level I–VI with only one intensity modulated treatment volume. The presented technique avoids to match conventional radiotherapy fields and IMRT fields, and therefore, reduce the risk of overdosage or underdosage at the matching line. Compared to conventional treatment techniques IMRT shows advantages in tumor dose and dose at the organs at risk.

In a case of partially resected sacral chordoma, the planning target volume (PTV) received 60 Gy and the gross target volume (GTV) 72 Gy using inversely planned, intensity-modulated, radiation therapy (IMRT). IMRT was compared with 3D-conformal radiotherapy (CRT). With IMRT, it was found that dose distribution is more homogeneous within the PTV outside the GTV and allows simultaneous dose escalation within the GTV. The volume of bowel receiving a dose higher than 40 Gy was reduced from 400 cc with CRT to 220 cc with IMRT. If particle therapy is not available, IMRT seems to be a promising alternative in the treatment of sacral chordomas.

Inverse planning and IMRT are methods with the potential to improve substantially clinical results in radiotherapy of prostate cancer. Available early clinical data demonstrate the feasibility and safety of high-dose IMRT for patients with localized prostate cancer and provide a proof-of-principle that this method improves dose conformality relative to tumor coverage and exposure to normal tissues.