Analysis of metabolic washout of positron emitters produced during carbon ion head and neck radiotherapy.

PURPOSE: Particle Therapy Positron Emission Tomography (PT-PET) is a suitable method for verification of therapeutic dose delivery by measurements of irradiation-induced ß(+)-activity. Due to metabolic processes in living tissue ß(+)-emitters can be removed from the place of generation. This washout is a limiting factor for image quality. The purpose of this study is to investigate whether a washout model obtained by animal experiments is applicable to patient data. METHODS: A model for the washout has been developed by Mizuno et al. [Phys. Med. Biol. 48(15), 2269-2281 (2003)] and Tomitani et al. [Phys. Med. Biol. 48(7), 875-889 (2003)]. It is based upon measurements in a rabbit in living and dead conditions. This model was modified and applied to PET data acquired during the experimental therapy project at GSI Helmholtzzentrum für Schwerionenforschung Darmstadt, Germany. Three components are expected: A fast one with a half life of 2 s, a medium one in the range of 2-3 min, and a slow component of the order of 2-3 h. Ten patients were selected randomly for investigation of the fast component. To analyze the other two components, 12 one-of-a-kind measurements from a single volunteer patient are available. RESULTS: A fast washout on the time scale of a few seconds was not observed in the patient data. The medium processes showed a mean half life of 155.7 ± 4.6 s. This is in the expected range. Fractions of the activity not influenced by the washout were found. CONCLUSIONS: On the time scale of an in-beam or in-room measurement only the medium-time washout processes play a remarkable role. A slow component may be neglected if the measurements do not exceed 20 min after the end of the irradiation. The fast component is not observed due to the low relative blood filled volume in the brain.

Acute toxicity of combined photon IMRT and carbon ion boost for intermediate-risk prostate cancer - acute toxicity of 12C for PC.

BACKGROUND: Carbon ion ((12)C) therapy in the treatment of prostate cancer (PC) might result in an improved outcome as compared to low linear energy transfer irradiation techniques. In this study, we present the first interim report of acute side effects of the first intermediate-risk PC patients treated at the GSI (Gesellschaft für Schwerionenforschung) and the University of Heidelberg in an ongoing clinical phase I/II trial using combined photon intensity modulated radiation therapy (IMRT) and (12)C carbon ion boost. MATERIAL AND METHODS: Fourteen patients (planned accrual: 31 pts) have been treated within this trial so far. IMRT is prescribed to the median PTV at a dose of 30 × 2 Gy; (12)C boost is applied to the prostate (GTV) at a dose of 6 × 3 GyE using raster scan technique. Safety margins added to the clinical target volume were determined individually for each patient based on five independent planning computed tomography (CT)-scans. Acute gastrointestinal (GI) and genitourinary (GU) toxicity was assessed and documented according to the CTCAE Version 3.0. RESULTS: Radiotherapy was very well tolerated without any grade 3 or higher toxicity. Acute anal bleeding grade 2 was observed in 2/14 patients. Rectal tenesmus grade 1 was reported by three other patients. No further GI symptoms have been observed. Most common acute symptoms during radiotherapy were nocturia and dysuria CTC grade 1 and 2 (12/14). There was no severe acute GU toxicity. CONCLUSION: The combination of photon IMRT and carbon ion boost is feasible in patients with intermediate-risk PC. So far, the treatment has been well tolerated. Acute toxicity rates were in good accordance with data reported for high dose IMRT alone.

Temporal lobe reactions after radiotherapy with carbon ions: incidence and estimation of the relative biological effectiveness by the local effect model.

PURPOSE: To identify predictors for the development of temporal lobe reactions (TLR) after carbon ion radiation therapy (RT) for radiation-resistant tumors in the central nervous system and to evaluate the predictions of the local effect model (LEM) used for calculation of the biologically effective dose. METHODS AND MATERIALS: This retrospective study reports the TLR rates in patients with skull base chordomas and chondrosarcomas irradiated with carbon ions at GSI, Darmstadt, Germany, in the years 2002 and 2003. Calculation of the relative biological effectiveness and dose optimization of treatment plans were performed on the basis of the LEM. Clinical examinations and magnetic resonance imaging (MRI) were performed at 3, 6, and 12 months after RT and annually thereafter. Local contrast medium enhancement in temporal lobes, as detected on MRI, was regarded as radiation-induced TLR. Dose-volume histograms of 118 temporal lobes in 59 patients were analyzed, and 16 therapy-associated and 2 patient-associated factors were statistically evaluated for their predictive value for the occurrence of TLR. RESULTS: Median follow-up was 2.5 years (range, 0.3-6.6 years). Age and maximum dose applied to at least 1 cm(3) of the temporal lobe (D(max,V - 1 cm)3, maximum dose in the remaining temporal lobe volume, excluding the volume 1 cm(3) with the highest dose) were found to be the most important predictors for TLR. Dose response curves of D(max,V - 1 cm)3 were calculated. The biologically equivalent tolerance doses for the 5% and 50% probabilities to develop TLR were 68.8 ± 3.3 Gy equivalents (GyE) and 87.3 ± 2.8 GyE, respectively. CONCLUSIONS: D(max,V - 1 cm)3 is predictive for radiation-induced TLR. The tolerance doses obtained seem to be consistent with published data for highly conformal photon and proton irradiations. We could not detect any clinically relevant deviations between clinical findings and expectations based on predictions of the LEM.

High-resolution flow cytometry: a suitable tool for monitoring aneuploid prostate cancer cells after TMZ and TMZ-BioShuttle treatment.

If metastatic prostate cancer gets resistant to antiandrogen therapy, there are few treatment options, because prostate cancer is not very sensitive to cytostatic agents. Temozolomide (TMZ) as an orally applicable chemotherapeutic substance has been proven to be effective and well tolerated with occasional moderate toxicity especially for brain tumors and an application to prostate cancer cells seemed to be promising. Unfortunately, TMZ was inefficient in the treatment of symptomatic progressive hormone-refractory prostate cancer (HRPC). The reasons could be a low sensitivity against TMZ the short plasma half-life of TMZ, non-adapted application regimens and additionally, the aneuploid DNA content of prostate cancer cells suggesting different sensitivity against therapeutical interventions e.g. radiation therapy or chemotherapy. Considerations to improve this unsatisfying situation resulted in the realization of higher local TMZ concentrations, sufficient to kill cells regardless of intrinsic cellular sensitivity and cell DNA-index. Therefore, we reformulated the TMZ by ligation to a peptide-based carrier system called TMZ-BioShuttle for intervention. The modular-composed carrier consists of a transmembrane transporter (CPP), connected to a nuclear localization sequence (NLS) cleavably-bound, which in turn was coupled with TMZ. The NLS-sequence allows an active delivery of the TMZ into the cell nucleus after transmembrane passage of the TMZ-BioShuttle and intra-cytoplasm enzymatic cleavage and separation from the CPP. This TMZ-BioShuttle could contribute to improve therapeutic options exemplified by the hormone refractory prostate cancer. The next step was to syllogize a qualified method monitoring cell toxic effects in a high sensitivity under consideration of the ploidy status. The high-resolution flow cytometric analysis showed to be an appropriate system for a better detection and distinction of several cell populations dependent on their different DNA-indices as well as changes in proliferation of cell populations after chemotherapeutical treatment.

Treatment of glioblastoma multiforme cells with temozolomide-BioShuttle ligated by the inverse Diels-Alder ligation chemistry.

Recurrent glioblastoma multiforme (GBM), insensitive against most therapeutic interventions, has low response and survival rates. Temozolomide (TMZ) was approved for second-line therapy of recurrent anaplastic astrocytoma. However, TMZ therapy in GBM patients reveals properties such as reduced tolerability and inauspicious hemogram. The solution addressed here concerning GBM therapy consolidates and uses the potential of organic and peptide chemistry with molecular medicine. We enhanced the pharmacologic potency with simultaneous reduction of unwanted adverse reactions of the highly efficient chemotherapeutic TMZ. The TMZ connection to transporter molecules (TMZ-BioShuttle) was investigated, resulting in a much higher pharmacological effect in glioma cell lines and also with reduced dose rate. From this result we can conclude that a suitable chemistry could realize the ligation of pharmacologically active, but sensitive and highly unstable pharmaceutical ingredients without functional deprivation. The TMZ-BioShuttle dramatically enhanced the potential of TMZ for the treatment of brain tumors and is an attractive drug for combination chemotherapy.

Transporter molecules influence the gene expression in HeLa cells.

Progresses in biology and pharmacology led to highly specific bioactive substances, but their poor bioavailability at the site of action is a result of their physico-chemical properties. Various design approaches for transport carrier molecules facilitating the cellular entry of bioactive substances could help to reach their molecular target in cells and tissues. The transfer efficacy and the subsequent pharmacological effects of the cargo molecules are well investigated, but the investigations of effects of the carrier molecules themselves on the target cells or tissues remain necessary. A special attention should be paid to the differential gene expression, particularly in the interpretation of the data achieved by highly specific active pharmaceutical products. After application of transmembrane transport peptides, particularly the pAnt and also the HIV-1 Tat, cells respond with a conspicuous altered gene expression of at least three genes. The PKN1 gene was induced and two genes (ZCD1 and BSG) were slightly repressed. The genes and the chromosomes are described, the moderate differential gene expression graphed, and the ontology is listed.

Inverse-electron-demand Diels-Alder reaction as a highly efficient chemoselective ligation procedure: synthesis and function of a BioShuttle for temozolomide transport into prostate cancer cells.

Hormone-refractory prostate cancer (HRPC), insensitive to most cytostatic interventions, features low response rates and bad prognosis. Studies with HRPC treated with temozolomide (TMZ) showed a poor response and the results were discouraging. Therefore, TMZ has been considered to be ineffective for the treatment of patients with symptomatic and progressive HRPC. A solution to this problem is demonstrated in this study by combining proper solid-phase peptide synthesis and a chemoselective new 'click' chemistry based on the Diels-Alder reaction with 'inverse-electron-demand' (DAR(inv)) for the construction of a highly efficient TMZ-BioShuttle in which TMZ is ligated to transporter and subcellular address molecules. The transport to the targeted nuclei resulted in much higher efficiency and better pharmacological effects. The reformulation of TMZ to TMZ-BioShuttle achieved higher in vitro killing of prostate cancer cells. Accordingly, the potential of TMZ for the treatment of prostate tumors was dramatically enhanced even in a tenfold lower concentration than applied normally. This TMZ-BioShuttle may be well suited for combining chemotherapy with other cytostatic agents or radiation therapy.

Changes of prostate gland volume with and without androgen deprivation after intensity modulated radiotherapy - A follow-up study.

BACKGROUND AND PURPOSE: The shrinking effect of androgen deprivation therapy (ADT) on prostate volume is a known finding, but data on volume changes during radiotherapy are inconsistent. We examined patients with and without ADT undergoing intensity modulated radiotherapy (IMRT) and performed follow-up examinations to study volume changes before and after radiotherapy. METHODS AND MATERIALS: Prostate volumes between planning magnetic resonance imaging (MRI) and last available follow-up MRI were retrospectively determined in 39 patients. Median time interval between first and last MRI was 233days (range 126-813). Two observers performed volume measurements in consensus and were blind to the timing of MRI. Volume changes over MRI were determined using the ellipsoid formula. Data of patients with and without ADT were compared by a linear mixed model. RESULTS: Of 39 patients, 22 had ADT with a median duration of 5months (range 1-24). ADT patients showed lower prostate volume throughout the study period (-28% to 38%). Although individual shrinking effect was highly variable, patients treated with IMRT but without ADT showed a significantly larger volume reduction (26.1%) than patients with ADT (12.9%, p<0.05). CONCLUSIONS: Patients undergoing IMRT show definite prostate shrinkage. The rate is slowed down after 6months in both groups, whereas the volume reduction is significantly larger in patients without ADT. Nevertheless there is no adding effect of ADT+IMRT vs. IMRT alone.

TMZ-BioShuttle--a reformulated temozolomide.

There is a large number of effective cytotoxic drugs whose side effect profile, efficacy, and long-term use in man are well understood and documented over decades of use in clinical routine e.g. in the treatment of recurrent glioblastoma multiforme (GBM) and the hormone-refractory prostate cancer (HRPC). Both cancers are insensitive against most chemotherapeutic interventions; they have low response rates and poor prognoses. Some cytotoxic agents can be significantly improved by using modern technology of drug delivery or formulation. We succeeded to enhance the pharmacologic potency with simultaneous reduction of unwanted adverse reactions of the highly efficient chemotherapeutic temozolomide (TMZ) as an example. The TMZ connection to transporter molecules (TMZ-BioShuttle) resulted in a much higher pharmacological effect in glioma cell lines while using reduced doses. This permits the conclusion that a suitable chemistry could realize the ligation of pharmacologically active, but sensitive and highly unstable pharmaceutical ingredients without functional deprivation. The re-formulation of TMZ to TMZ-BioShuttle achieved a nearly 10-fold potential of the established pharmaceutic TMZ far beyond the treatment of brain tumors cells and results in an attractive reformulated drug with enhanced therapeutic index.

HIV-1 capsid assembly inhibitor (CAI) peptide: structural preferences and delivery into human embryonic lung cells and lymphocytes.

The Human immunodeficiency virus 1 derived capsid assembly inhibitor peptide (HIV-1 CAI-peptide) is a promising lead candidate for anti-HIV drug development. Its drawback, however, is that it cannot permeate cells directly. Here we report the transport of the pharmacologically active CAI-peptide into human lymphocytes and Human Embryonic Lung cells (HEL) using the BioShuttle platform. Generally, the transfer of pharmacologically active substances across membranes, demonstrated by confocal laser scanning microscopy (CLSM), could lead to a loss of function by changing the molecule's structure. Molecular dynamics (MD) simulations and circular dichroism (CD) studies suggest that the CAI-peptide has an intrinsic capacity to form a helical structure, which seems to be critical for the pharmacological effect as revealed by intensive docking calculations and comparison with control peptides. This coupling of the CAI-peptide to a BioShuttle-molecule additionally improved its solubility. Under the conditions described, the HIV-1 CAI peptide was transported into living cells and could be localized in the vicinity of the mitochondria.

BioShuttle-mediated plasmid transfer.

An efficient gene transfer into target tissues and cells is needed for safe and effective treatment of genetic diseases like cancer. In this paper, we describe the development of a transport system and show its ability for transporting plasmids. This non-viral peptide-based BioShuttle-mediated transfer system consists of a nuclear localization address sequence realizing the delivery of the plasmid phNIS-IRES-EGFP coding for two independent reporter genes into nuclei of HeLa cells. The quantification of the transfer efficiency was achieved by measurements of the sodium iodide symporter activity. EGFP gene expression was measured with Confocal Laser Scanning Microscopy and quantified with biostatistical methods by analysis of the frequency of the amplitude distribution in the CLSM images. The results demonstrate that the "BioShuttle"-Technology is an appropriate tool for an effective transfer of genetic material carried by a plasmid.

Induced and repressed genes after irradiation sensitizing by pentoxyphylline.

Aim in cancer therapy is to increase the therapeutic ratio eliminating the disease while minimizing toxicity to normal tissues. Radiation therapy is a main component in targeting cancer. Radiosensitizing agents like pentoxyphylline (PTX) have been evaluated to improve radiotherapy. Commonly, cells respond to radiation by the activation of specific early and late response genes as well as by inhibition of genes, which are expressed under normal conditions. A display of the genetic distinctions at the level of transcription is given here to characterize the molecular events underlying the radiosensitizing mechanisms. The method of suppression subtractive hybridization allows the visualization of both induced and repressed genes in irradiated cells compared with cells sensitized immediately after irradiation. The genes were isolated by cDNA-cloning, differential analysis and sequence similarity search. Genes involved in protein synthesis, metabolism, proteolysis and transcriptional regulation were detected. It is important that genes like KIAA280, which were only known as unidentified EST sequences before without function, but inaccessible by array technology were recovered as functional genes. Database searches for PTX-induced genes detected a human mRNA completely unknown. In case of suppressed genes, we detected several mRNAs; one thereof shows homology to a hypothetical protein possibly involved in signal transduction. A further mRNA encodes the protein BM036 supposed to associate with the E2F transcription factor. A hypothetical protein H41 was detected, which may repress the Her-2/neu receptor influencing breast cancer, gliomas and prostate tumors. Radiation combined with PTX may lead to a better prognosis by down regulation of the Her-2/neu, which will be proven by clinical studies in the near future.

Carbon ion radiotherapy of skull base chondrosarcomas.

PURPOSE: To evaluate the effectiveness and toxicity of carbon ion radiotherapy in chondrosarcomas of the skull base. PATIENTS AND METHODS: Between November 1998 and September 2005, 54 patients with low-grade and intermediate-grade chondrosarcomas of the skull base have been treated with carbon ion radiation therapy (RT) using the raster scan technique at the Gesellschaft für Schwerionenforschung in Darmstadt, Germany. All patients had gross residual tumors after surgery. Median total dose was 60 CGE (weekly fractionation 7 x 3.0 CGE). All patients were followed prospectively in regular intervals after treatment. 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: Median follow-up was 33 months (range, 3-84 months). Only 2 patients developed local recurrences. The actuarial local control rates were 96.2% and 89.8% at 3 and 4 years; overall survival was 98.2%at 5 years. Only 1 patient developed a mucositis CTCAE Grade 3; the remaining patients did not develop any acute toxicities >CTCAE Grade 2. Five patients developed minor late toxicities (RTOG/EORTC Grades 1-2), including bilateral cataract (n = 1), sensory hearing loss (n = 1), a reduction of growth hormone (n = 1), and asymptomatic radiation-induced white matter changes of the adjacent temporal lobe (n = 2). Grade 3 late toxicity occurred in 1 patient (1.9%) only. CONCLUSIONS: Carbon ion RT is an effective treatment for low- and intermediate-grade chondrosarcomas of the skull base offering high local control rates with low toxicity.

Diffusion tensor imaging in primary brain tumors: reproducible quantitative analysis of corpus callosum infiltration and contralateral involvement using a probabilistic mixture model.

Diffusion tensor imaging (DTI) has been advocated as a promising tool for delineation of the extent of tumor infiltration by primary brain tumors. First reports show conflicting results mainly due to difficulties in reproducible determination of DTI-derived parameters. A novel method based on probabilistic voxel classification for a user-independent analysis of DTI-derived parameters is presented and tested in healthy controls and patients with primary brain tumors. The proposed quantification method proved to be highly reproducible both in healthy controls and patients. Fiber integrity in the corpus callosum (CC) was measured using this quantification method, and the profiles of fractional anisotropy (FA) provided additional information of the possible extent of infiltration of primary brain tumors when compared to conventional imaging. This yielded additional information on the nature of ambiguous contralateral lesions in patients with primary brain tumors. The results show that DTI-derived parameters can be determined reproducibly and may have a strong impact on evaluation of contralateral extent of primary brain tumors.

Therapy strategies for locally advanced adenoid cystic carcinomas using modern radiation therapy techniques.

BACKGROUND: The authors evaluated whether modern photon techniques, such as stereotactic fractionated radiation therapy (FSRT) or intensity-modulated RT, outweighed the biologic advantages of high-linear-energy transfer RT in the treatment of patients with locally advanced adenoid cystic carcinomas (ACC) that infiltrated the skull base or the orbit. METHODS: Between June 1995 and December 2003, 63 patients with ACC were treated with modern RT techniques at the University of Heidelberg. The treatment results achieved with modern photon techniques alone were compared with the results achieved with combined photon RT and a carbon ion boost. Twenty-nine patients (Group A) were treated with a combination of photon RT and a carbon ion boost. Thirty-four patients (Group B) received photon RT alone. RESULTS: The median follow-up was 16 months for Group A and 24 months for Group B. Locoregional control rates at 2 years and 4 years were 77.5% and 77.5% for Group A and 72.2% and 24.6% for Group B, respectively (P = 0.08; log-rank test). Disease-free and overall survival rates at 2 years/4 years were 71.5%/53% and 86.6%/75.8% for Group A and 69.2%/23% and 77.9%/77.9% for Group B, respectively. Rates for severe late toxicity were < 5% for both groups. CONCLUSIONS: Modern RT techniques allowed the safe delivery of high target doses to patients with locally advanced ACC. Late toxicity rates were kept lower compared with the historic neutron therapy data. A combination of modern photon RT and carbon ion RT seemed to be advantageous, with a trend toward higher locoregional control rates compared with modern photon RT alone.

Evaluation of therapeutic potential of heavy ion therapy for patients with locally advanced prostate cancer.

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 cm3. 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 cm3. 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.

Carbon ion radiation therapy for chordomas and low grade chondrosarcomas--current status of the clinical trials at GSI.

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.

Influence of setup errors on spinal cord dose and treatment plan quality for cervical spine tumours: a phantom study for photon IMRT and heavy charged particle radiotherapy.

Tumours partly surrounding the cervical spine may be treated by conformal radiotherapy (RT) using intensity-modulated RT (IMRT) with photons or heavy charged particle RT. For both, a high setup accuracy is required to spare the radiosensitive spinal cord, if a high dose is to be delivered. A phantom study was performed to determine the variation of the dose to the spinal cord surface by predefined setup errors. The measured doses were compared to those calculated by the treatment planning programme. The influence of systematic setup errors on characteristic parameters of the treatment plan quality was quantified. The largest variation of the mean and maximum doses to the spinal cord due to setup errors was significantly larger for carbon ions than for IMRT (mean: 11.9% versus 3.9%, max: 29.2% versus 10.8% of the prescribed dose). For the comparison of measured and calculated doses, mean deviations of 3% (IMRT) and 6% (carbon ions) of the prescribed dose were obtained. These deviations have to be considered, when the spinal cord dose is assessed from the treatment plan and they may also influence the dose prescription. Carbon ions yield better values for coverage (99.9% versus 93.1%) and conformality (110% versus 126%) of the PTV as compared to IMRT, while the spinal cord is better spared. Dose distributions produced with carbon ions, however, are more sensitive to setup errors, which have to be considered during treatment.

Stereotactic intensity modulated radiation therapy and inverse treatment planning for tumors of the head and neck region: clinical implementation of the step and shoot approach and first 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 64.1 Gy. The mean total dose of microscopic disease ranged between 55.2 and 60.1 Gy. 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 18 min. 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.