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Purpose Purpose of this study was to investigate overall survival in recurrent glioblastoma treated with either carbon ion reirradiation or photon reirradiation. Materials and methods In this retrospective study we evaluated 78 consecutive patients with recurrent IDH (Isocitrate dehydrogenase)-wildtype glioblastoma (38 patients carbon ion re-radiotherapy, 40 patients photon re-radiotherapy) treated with either carbon ion reirradiation or stereotactic photon reirradiation. 45 Gy (RBE; 15 fractions) carbon ion reirradiation (CIRT) or 39 Gy (13 fractions) photon reirradiation (FSRT) was administered, respectively. Overall survival was investigated with respect to histological, clinical, and epidemiological features. Kaplan–Meier and multivariate Cox statistics were calculated. A propensity score-matched analysis of the FSRT and CIRT groups using variables from a validated prognosis score was carried out. Results The type of reirradiation (CIRT vs. FSRT) significantly influenced overall survival—8.0 months vs. 6.5 months (univariate: p = 0.046)—and remained an independent prognostic factor in multivariate analysis (p = 0.017). Propensity score-adjusted analysis with CIRT versus FSRT as the dependent variable yielded a significant overall survival advantage for the CIRT group (median OS 8.9 versus 7.2 months, p = 0.041, 1‑year survival 29 versus 10%). Adverse events (AE) were evaluated for both subgroups. For the FSRT group no toxicity ≥ grade 4 occurred. For the CIRT subgroup no grade 5 AE occurred, but 1 patient developed a grade 4 radionecrosis. We encountered 4 grade 3 toxicities. One patient developed a zoster at the trunk, 2 progressed in their paresis, and 1 featured progressive dysesthesia. Conclusion In conclusion, carbon ion treatment is a safe and feasible treatment option for recurrent glioblastoma. Due to the retrospective nature of the study and two different dose levels for CIRT or FSRT, the improved outcome in CIRT reirradiation might be an effect of higher biological impact from carbon ions or a simple dose-escalation effect. This hypothesis needs prospective testing in larger patient cohorts. A prospective phase III randomized trial is in preparation at our center.

Purpose The adenoid cystic carcinoma (ACC), Erbitux, and Particle Therapy (ACCEPT) phase 1/2 trial (NCT01192087) evaluated a combined-modality approach (concurrent cetuximab and intensity modulated radiation therapy with carbon ion boost) for newly diagnosed nonmetastatic head and neck ACC. Methods and Materials Twenty-three patients with ACC were enrolled between June 2012 and June 2017 after initial diagnosis or postoperatively. All received a 400 mg/m2 cetuximab loading dose a week before radiation therapy, followed by weekly 250 mg/m2 doses starting on the first day of radiation therapy. The carbon ion radiation therapy boost was 24 Gy (relative biological effectiveness) in 8 daily fractions, followed by intensity modulated radiation therapy (54 Gy). The primary endpoint was safety and feasibility (defined based on Common Terminology Criteria for Adverse Events grade ≥3 events). Secondary endpoints included local and distant relapse, disease-free survival, and overall survival. Results Disease was most commonly in the paranasal sinuses (30%), palate (17%), and nasopharynx (17%). Nine (39%) patients underwent surgery (R1: 22%, R2: 78%). Median follow-up was 38.5 months. No patients experienced grade 4 to 5 events. Rates of grade 3 rash and radiation dermatitis were 17% and 22%, respectively. Grade 2 and 3 mucositis and dysgeusia occurred in 43% and 48% and in 9% and 0%, respectively. Grade 2 to 3 dysphagia and xerostomia were present in 43% and 4% and in 26% and 0%, respectively. At last follow-up, 5 (22%) patients experienced in-field relapse and 6 (26%) developed distant metastases. The 3-year disease-free survival was 67%, and median overall survival was 54 months. Conclusions Outcomes of this trial were satisfactory. Although the trial did not meet the predefined criteria of feasibility owing to the comparatively high rates of grade 3 dermatitis, numbers are comparable to existing data on cetuximab + radiation therapy.

Background Patients with recurrent glioma after prior radiotherapy have a poor prognosis. Carbon ion beam radiotherapy offers highly conformal dose distributions and more complex biological radiation effects eventually resulting in optimized normal tissue sparing and improved outcome. The aim of this study was to analyze toxicity, local control and overall survival after reirradiation of recurrent high-grade glioma with carbon ion radiotherapy. Methods Between 10/2015 and 12/2018, 30 patients (median age: 59 years) with recurrent high-grade glioma were reirradiated with carbon ion beams and retrospectively analyzed. Diagnosis of recurrent glioma was based on magnetic resonance imaging. Thirteen patients had repeated resection prior to reirradiation and 24 patients underwent additional chemotherapy. The median initial radiation dose was 60 Gy and the median time interval between the initial and repeated radiotherapy was 10 months. The reirradiation dose was 45 Gy (relative biological effectiveness) applied in 15 fractions. All patients received regular follow-up imaging after reirradiation. Kaplan-Meier estimation, log rank test and Cox regression analysis were used for statistical assessment. Results Applying common toxicity criteria, there were no grade 5 or 4 adverse events, while 8 patients showed grade 3 adverse events. The median follow-up after reirradiation was 11 months and the median overall survival after diagnosis of recurrent high-grade glioma was 13 months. The 6-, 12- and 24-month overall survival rates after diagnosis of recurrent high-grade glioma were 76%, 50% and 19%, respectively. Upon multivariate Cox regression analysis, a Ki67 score of the initial tumor histology of less than 20% was prognostic. Repeated resection or chemotherapy for the recurrent disease did not result in significantly prolonged survival. Conclusion Carbon ion reirradiation in recurrent high-grade glioma is safe and feasible. No radiation-associated grade 4 toxicities were documented and treatment was tolerated well.

Background: Patients with multiple brain metastases (BMs) from malignant melanoma have a poor prognosis. Recent developments in radiation techniques allow simultaneous integrated boost (SIB) concepts while sparing organs at risk. Data on conventional versus dose-escalated radiation approaches in multiple BMs from malignant melanoma are warranted. Methods: In this prospective, single-center, randomized two-armed study (trial ID: DRKS00005127), patients with multiple BMs from malignant melanoma were treated with either conventional whole-brain radiotherapy (WBRT) applying 30 Gy in 10 fractions (standard arm) or helical tomotherapy applying 30 Gy to the whole brain with an integrated boost to metastases of 50 Gy in 10 fractions and sparing of the hippocampus (HA-WBRT, experimental arm). The primary endpoint was treatment-related toxicity, while secondary endpoints were imaging response, intracerebral progression-free survival (PFS), overall survival (OS) and quality of life. Results: The study was stopped early due to slow patient recruitment. A total number of 7 patients were enrolled (standard arm n=3, experimental arm n=4), and were followed-up for a median time of 5 months between August 2013 and July 2017. All patients were treated according to protocol. The median OS, intracerebral PFS and follow-up time were 5 months, 2 months and 5 months, respectively. The local control in every individual BM was significantly longer in the experimental versus the standard arm. No patient developed radiation-related high-grade toxicities. Conclusion: HA-WBRT with SIB results in improved local control in the individual melanoma BMs without radiation-associated high-grade toxicities. Survival times were comparable to published data.

Background Neurosurgical resection is recommended for symptomatic brain metastases, in oligometastatic patients or for histology acquisition. Without adjuvant radiotherapy, roughly two-thirds of the patients relapse at the resection site within 24 mo, while the risk of new metastases in the untreated brain is around 50%. Adjuvant whole-brain radiotherapy (WBRT) can reduce the risk of both scenarios of recurrence significantly, although the associated neurocognitive toxicity is substantial, while stereotactic radiotherapy (SRT) improves local control at comparably low toxicity. Objective To compare locoregional control and treatment-associated toxicity for postoperative SRT and WBRT after the resection of 1 brain metastasis in a single-center prospective randomized study. Methods Fifty patients will be randomized to receive either hypofractionated SRT of the resection cavity and single- or multisession SRT of all unresected brain metastases (up to 10 lesions) or WBRT. Patients will be followed-up regularly and the primary endpoint of neurological progression-free survival will be assessed by magnetic resonance imaging (MRI). Quality of life and neurocognition will be assessed in 3-mo intervals using standardized tests and EORTC questionnaires. Expected outcomes We expect to show that postoperative SRT of the resection cavity and further unresected brain metastases is a valid means of improving locoregional control over observation at less neurocognitive toxicity than caused by WBRT. Discussion The present study is the first to compare locoregional control as well as neurocognitive toxicity for postoperative SRT and WBRT in patients with up to 10 metastases, while utilizing a highly sensitive and standardized MRI protocol for treatment planning and follow-up.

To investigate the incidence rate, time-to-onset and recovery, MRI morphology and occurrence of insufficiency fractures in radiation-induced changes in the sacrum following pelvic radiotherapy. 410 patients with pelvic malignancies treated with radiotherapy were reviewed. Follow-up was 1–124 months (mean 22 months). Serial MRI (average four studies/patient) were analysed using a new semi-quantitative score (Radiation-Induced Sacral Changes=RISC). A size category (I/II/III), a type category for MR signal morphologies (a/b/c) and sacral insufficiency fractures (+/-) were applied. Seventy-two patients (17.6 %) were found to have new pathological signal changes. Radiation osteitis was documented in 83.3 % (60/72, RISC stage a + b), and definite osteonecrosis (stage c) in 12 patients (16.7 %, 12/72). Thirty-one patients (43.1 %) had sacral insufficiency fractures. Initial bone marrow signal changes were found 1–35 months (median 4 months) after radiotherapy. The maximum manifestation of radiation-induced signal changes occurred after 1–35 months (mean 11 months). Fifty-six cases (77.8 %) showed a significant signal recovery within 16.5 months. Radiation-induced bone marrow changes appear with a high incidence at the sacrum with an early onset and frequent recovery. The majority presented a pattern of radiation osteitis, whereas osteoradionecrosis was proportionately rare. • Radiation-induced sacral bone marrow changes appear frequently (17.6 %) following pelvic radiotherapy. • Insufficiency fractures are common late effects (43 %). • Radiation osteitis develops early (4 mo), with recovery between 16.5 and 39.5 months. • Definite radiological osteoradionecrosis is proportionately rare (3 %). • A 3-stage classification system simplifies and standardizes the morphological disease staging.

Background The current study compares the results of irradiation with protons and irradiation with carbon ions via a raster scan technique in patients with G1 and G2 skull base chondrosarcomas. Methods Between 2009 and 2014, a total of 101 patients (40 men and 61 women) with a median age of 44 years (range, 19-77 years) were irradiated with carbon ions (79 patients) or protons (22 patients) via a raster scan technique at the Heidelberg Ion Beam Therapy Center. The median total dose was 60 Gy (relative biological effectiveness [RBE]) at 3 Gy per fraction for carbon ions and 70 Gy (RBE) at 2 Gy per fraction for protons. The median boost planning target volume was 38 cm3 (range, 8-133 cm3 ). Overall survival (OS) and local control (LC) were evaluated with the Kaplan-Meier method. Results The median follow-up period was 40 months (range, 0.8-78.1 months). At the start of the irradiation, all patients had residual macroscopic tumors. Five patients (5%) developed a local recurrence during the follow-up. The 1-, 2-, and 4-year LC rates were 100%, 100%, and 100%, respectively, for protons and 98.6%, 97.2%, and 90.5%, respectively, for carbon ions. The OS rates during the same periods of time were 100%, 100%, and 100%, respectively, for protons and 100%, 98.5%, and 92.9%, respectively, for carbon ions. An age ≤ 44 years was associated with a trend for a better outcome. No toxicity worse than Common Toxicity Criteria grade 3 was observed after treatment. Conclusions No significant difference between carbon ions and protons in the therapy of skull base chondrosarcoma could be detected in these initial retrospective results. Cancer 2018;124:2036-44. © 2018 American Cancer Society.

Xerostomia is a common side effect of radiotherapy resulting from excessive irradiation of salivary glands. Typically, xerostomia is modeled by the mean dose-response characteristic of parotid glands and prevented by mean dose constraints to either contralateral or both parotid glands. The aim of this study was to investigate whether normal tissue complication probability (NTCP) models based on the mean radiation dose to parotid glands are suitable for the prediction of xerostomia in a highly conformal low-dose regime of modern intensity-modulated radiotherapy (IMRT) techniques.We present a retrospective analysis of 153 head and neck cancer patients treated with radiotherapy. The Lyman Kutcher Burman (LKB) model was used to evaluate predictive power of the parotid gland mean dose with respect to xerostomia at 6 and 12 months after the treatment. The predictive performance of the model was evaluated by receiver operating characteristic (ROC) curves and precision-recall (PR) curves.Average mean doses to ipsilateral and contralateral parotid glands were 25.4 Gy and 18.7 Gy, respectively. QUANTEC constraints were met in 74% of patients. Mild to severe (G1+) xerostomia prevalence at both 6 and 12 months was 67%. Moderate to severe (G2+) xerostomia prevalence at 6 and 12 months was 20% and 15%, respectively. G1 + xerostomia was predicted reasonably well with area under the ROC curve ranging from 0.69 to 0.76. The LKB model failed to provide reliable G2 + xerostomia predictions at both time points.Reduction of the mean dose to parotid glands below QUANTEC guidelines resulted in low G2 + xerostomia rates. In this dose domain, the mean dose models predicted G1 + xerostomia fairly well, however, failed to recognize patients at risk of G2 + xerostomia. There is a need for the development of more flexible models able to capture complexity of dose response in this dose regime.

Background/aim In percutaneous radiotherapy dose-distribution and volumetric-load of normal tissue varies in different radiation-techniques. Haematotoxicity may lead to deficiencies of the immune and blood system or to secondary malignancies. Therefore, regular blood-counts are carried out during fractionated radiotherapy. The aim was to investigate patient haemogram courses during radiotherapy of localised prostate-cancer treated with different radiation-techniques (n=3). Patients and methods In this prospective study, blood count changes were examined during fractionated radiotherapy (3D-conformal-RT/step-and-shoot-IMRT/helical-IMRT) on the prostate-region in localised prostate-cancer cases (n=50). Results The whole patient group displayed a small but significant reduction in leukocytes. This reduction was higher in the two IMRT groups compared to the 3D-group but without any case of leukopenia. Haemoglobin- or thrombocyte-levels did not significantly change. Conclusion Regardless of the delivery mode used, localised fractionated irradiation of prostate region did not cause any clinically relevant haemogram changes in this study. These findings question the necessity of regular blood counts during fractionated radiotherapy of the prostate region for patients without any risk factors.

Purpose: Due to the sharp gradients of intensity-modulated radiotherapy (IMRT) dose distributions, treatment uncertainties may induce substantial deviations from the planned dose during irradiation. Here, we investigate if the planned mean dose to parotid glands in combination with the dose gradient and information about anatomical changes during the treatment improves xerostomia prediction in head and neck cancer patients. Materials and methods: Eighty eight patients were retrospectively analyzed. Three features of the contralateral parotid gland were studied in terms of their association with the outcome, i.e., grade ≥ 2 (G2) xerostomia between 6 months and 2 years after radiotherapy (RT): planned mean dose (MD), average lateral dose gradient (GRADX), and parotid gland migration toward medial (PGM). PGM was estimated using daily megavoltage computed tomography (MVCT) images. Three logistic regression models where analyzed: based on (1) MD only, (2) MD and GRADX, and (3) MD, GRADX, and PGM. Additionally, the cohort was stratified based on the median value of GRADX, and a univariate analysis was performed to study the association of the MD with the outcome for patients in low- and high-GRADX domains. Results: The planned MD failed to recognize G2 xerostomia patients (AUC = 0.57). By adding the information of GRADX (second model), the model performance increased to AUC = 0.72. The addition of PGM (third model) led to further improvement in the recognition of the outcome (AUC = 0.79). Remarkably, xerostomia patients in the low-GRADX domain were successfully identified (AUC = 0.88) by the MD alone. Conclusions: Our results indicate that GRADX and PGM, which together serve as a proxy of dosimetric changes, provide valuable information for xerostomia prediction.

Purpose To evaluate whether quantitative susceptibility (QSM) may be used as an alternative to computed tomography (CT) to detect calcification in prostate cancer patients. Materials and Methods Susceptibility map calculation was performed using 3D gradient echo magnetic resonance imaging (MRI) data from 26 patients measured at 3T who previously received a planning CT of the prostate. Phase images were unwrapped using Laplacian-based phase unwrapping, the background field was removed with the V-SHARP method, and susceptibility maps were calculated with the iLSQR method. Two blinded readers were asked to identify peri- and intraprostatic calcifications. Results Average mean and minimum susceptibility values (referenced to iliopsoas muscle) of calcifications were −0.249 ± 0.179 ppm and –0.551 ± 0.323 ppm, and average mean and maximum intensities in CT images were 319 ± 164 HU and 679 ± 392 HU. Twenty-one and 17 out of 22 prostatic calcifications were identified using susceptibility maps and magnitude images, respectively, as well as more than half of periprostatic phleboliths depicted by CT. Calcifications in the prostate and its periphery were quantitatively differentiable from noncalcified prostate tissue in CT (mean values for calcifications / for noncalcified tissue: 71 to 649 / –1 to 83 HU) and in QSM (mean values for calcifications / for noncalcified tissue: –0.641 to 0.063 / –0.046 to 0.181 ppm). Moreover, there was a significant correlation between susceptibility values and CT image intensities for calcifications (P < 0.004). Conclusion Prostatic calcifications could be well identified with QSM. Susceptibility maps can be easily obtained from clinical prostate MR protocols that include a 3D gradient echo sequence, rendering it a promising technique for detection and quantification of intraprostatic calcifications. Level of Evidence: 1 J. Magn. Reson. Imaging 2017;45:889–898.

To compare patterns of prostate-specific antigen (PSA) response following stereotactic body radiation therapy (SBRT), high-dose-rate (HDR) brachytherapy, and conventionally fractionated intensity modulated radiation therapy (IMRT) in patients with low- or intermediate-risk prostate cancer (CaP).Eligible study patients included 439 patients with low- or intermediate-risk prostate cancer who were treated with radiation therapy (RT) alone between 2003 and 2013, remained free of biochemical recurrence, and had at least 2 PSA values within the first year following RT. Of these, 130 were treated with SBRT, 220 with HDR brachytherapy, and 89 with IMRT. Multivariate regression analysis was used to compare PSA nadirs (nPSA), time to nPSA, and PSA bounce parameters among the 3 modalities. Indicator variable analysis was used to develop empirical models of PSA decay using the treatment modalities as indicator variables.Significantly more patients treated with SBRT or HDR brachytherapy achieved raw nPSAs of0.5 ng/mL compared with patients treated with IMRT (76.2% and 75.9% vs 44.9%, respectively; P.0001 for SBRT or HDR brachytherapy vs IMRT). On multivariate analysis, nPSA was significantly lower with SBRT and HDR compared with IMRT (P.0001). Time to nPSA and bounce parameters was not significantly different among IMRT, SBRT, and HDR. Overall, SBRT and HDR brachytherapy caused significantly larger PSA decay rates (P.001). When truncating follow-up at 1000 days, the corresponding decay rates were larger for all 3 modalities, with no significant differences between them.Stereotactic body radiation therapy and HDR brachytherapy produce lower nPSAs than IMRT. Within 1000 days of follow-up, the modalities produce similar rates of PSA decay; subsequently, decay continues (albeit at a slower pace) after SBRT and HDR brachytherapy but plateaus with IMRT. Because nPSA is a validated predictor of long-term outcome, these data not only suggest a distinct radiobiological effect with SBRT and HDR brachytherapy, but also predict for clinical outcomes that might equal or surpass those of IMRT.

Purpose High-dose-rate (HDR) brachytherapy was originally used with external beam radiation therapy (EBRT) to increase the dose to the prostate without injuring the bladder or rectum. Numerous studies have reported HDR brachytherapy is safe and effective. We adapted it for use without EBRT for cases not requiring lymph node treatment. Patients and Methods We entered the patient demographics, disease characteristics, and treatment parameters into a prospective registry and serially added follow-up data for 448 men with low-risk (n=288) and intermediate-risk (n=160) prostate cancer treated from 1996 to 2009. Their median age was 64 years (range 42-90). The median prostate-specific antigen (PSA) level was 6.0 ng/mL (range 0.2-18.2). The Gleason score was ≤6 in 76% and 7 in 24%. The median dose was 43.5 Gy in 6 fractions. The clinical and biochemical disease control and survival rates were calculated. Adverse events were graded according to the Common Toxicity Criteria of Adverse Events. Results The median follow-up period was 6.5 years (range 0.3-15.3). The actuarial 6- and 10-year PSA progression-free survival was 98.6% (95% confidence interval [CI] 96.9%-99.4%) and 97.8% (95% CI 95.5%-98.9%). Overall survival at 10 years was 76.7% (95% CI 69.9%-82.2%). The local control, distant metastasis-free survival, and cause-specific survival were 99.7% (95% CI 97.9%-99.9%), 98.9% (95% CI 96.3%-99.7%), and 99.1% (95% CI 95.8%-99.8%). T stage, initial PSA level, Gleason score, National Comprehensive Cancer Network risk group, patient age, and androgen deprivation therapy did not significantly correlate with disease control or survival. No late grade 3 to 4 rectal toxicities developed. Late grade 3 to 4 genitourinary toxicity occurred in 4.9% (grade 3 in 4.7%). Conclusions HDR monotherapy is a safe and highly effective treatment of low- and intermediate-risk prostate cancer.

Purpose: The purpose of this study is to investigate whether machine learning with dosiomic, radiomic, and demographic features allows for xerostomia risk assessment more precise than normal tissue complication probability (NTCP) models based on the mean radiation dose to parotid glands. Material and methods: A cohort of 153 head-and-neck cancer patients was used to model xerostomia at 0-6 months (early), 6-15 months (late), 15-24 months (long-term), and at any time (a longitudinal model) after radiotherapy. Predictive power of the features was evaluated by the area under the receiver operating characteristic curve (AUC) of univariate logistic regression models. The multivariate NTCP models were tuned and tested with single and nested cross-validation, respectively. We compared predictive performance of seven classification algorithms, six feature selection methods, and ten data cleaning/class balancing techniques using the Friedman test and the Nemenyi post hoc analysis. Results: NTCP models based on the parotid mean dose failed to predict xerostomia (AUCs < 0.60). The most informative predictors were found for late and long-term xerostomia. Late xerostomia correlated with the contralateral dose gradient in the anterior posterior (AUC = 0.72) and the right left (AUC = 0.68) direction, whereas long-term xerostomia was associated with parotid volumes (AUCs > 0.85), dose gradients in the right left (AUCs > 0.78), and the anterior posterior (AUCs > 0.72) direction. Multivariate models of long-term xerostomia were typically based on the parotid volume, the parotid eccentricity, and the dose volume histogram (DVH) spread with the generalization AUCs ranging from 0.74 to 0.88. On average, support vector machines and extra-trees were the top performing classifiers, whereas the algorithms based on logistic regression were the best choice for feature selection. We found no advantage in using data cleaning or class balancing methods. Conclusion: We demonstrated that incorporation of organ- and dose-shape descriptors is beneficial for xerostomia prediction in highly conformal radiotherapy treatments. Due to strong reliance on patient-specific, dose-independent factors, our results underscore the need for development of personalized data-driven risk profiles for NTCP models of xerostomia. The facilitated machine learning pipeline is described in detail and can serve as a valuable reference for future work in radiomic and dosiomic NTCP modeling.

In radiotherapy, in vivo measurement of dose distribution within patients' lymphocytes can be performed by detecting gamma-H2AX foci in lymphocyte nuclei. This method can help in determining the whole-body dose. Options for risk estimations for toxicities in normal tissue and for the incidence of secondary malignancy are still under debate. In this investigation, helical tomotherapy (TOMO) is compared with step-and-shoot IMRT (SSIMRT) of the prostate gland by measuring the dose distribution within patients' lymphocytes. In this prospective study, blood was taken from 20 patients before and 10 min after their first irradiation fraction for each technique. The isolated leukocytes were fixed 2 h after radiation. DNA double-stranded breaks in lymphocyte nuclei were stained immunocytochemically using anti-gamma-H2AX antibodies. Gamma-H2AX foci distribution in lymphocytes was determined for each patient. Using a calibration line, dose distributions in patients' lymphocytes were determined by studying the gamma-H2AX foci distribution, and these data were used to generate a cumulative dose–lymphocyte histogram (DLH). Measured in vivo (DLH), significantly fewer lymphocytes indicated low-dose exposure (

To evaluate the safety and efficacy of reirradiation with carbon ions in patients with relapse of skull base chordoma and chondrosarcoma.Reirradiation with carbon ions was performed on 25 patients with locally recurrent skull base chordoma (n = 20) or chondrosarcoma (n = 5). The median time between the last radiation exposure and the reirradiation with carbon ions was 7 years. In the past, 23 patients had been irradiated once, two patients twice. Reirradiation was delivered using the active raster scanning method. The total median dose was 51.0 GyE carbon ions in a weekly regimen of five to six fractions of 3 GyE. Local progression-free survival (LPFS) was evaluated using the Kaplan-Meier method; toxicity was evaluated using the NCI Common Terminology Criteria for Adverse Events (CTCAE v.4.03).The treatment could be finished in all patients without interruption. In 80% of patients, symptom control was achieved after therapy. The 2-year-LPFS probability was 79.3%. A PTV volume of 100 ml or a total dose of 51 GyE was associated with a superior local control rate. The therapy was associated with low acute toxicity. One patient developed grade 2 mucositis during therapy. Furthermore, 12% of patients had tympanic effusion with mild hypacusis (grade 2), while 20% developed an asymptomatic temporal lobe reaction after treatment (grade 1). Only one patient showed a grade 3 osteoradionecrosis.Reirradiation with carbon ions is a safe and effective method in patients with relapsed chordoma and chondrosarcoma of the skull base.

AimTo give a technical description and present the dosimetric proporties of the total skin electron beam technique implemented at Heidelberg University Hospital.BackgroundTechniques used for total skin electron beam irradiation were developed as early as in the 1960s to 1980s and have, since then, hardly changed. However, new measurements of the established methods allow deeper insight into the dose distributions and reasons for possible deviations from uniform dose.Materials and methodsThe TSEI technique applied at Heidelberg University Hospital since 1992 consists of irradiating the patient with a superposition of two beams of low energy electrons at gantry angles of 72° and 108° while he is rotating in a standing position on a turntable at 370cm distance from the accelerator. The energy of the electron beam is degraded to 3.9MeV by passing through an attenuator of 6mm of Perspex. A recent re-measurement of the dose distribution is presented using modern dosimetry tools like a linear array of ionization chambers in combination with established methods like thermoluminescent detectors and film dosimetry.ResultsThe measurements show a strong dependence of dose uniformity on details of the setup like gantry angles.ConclusionsDose uniformity of −4/+8% to the majority of the patient's skin can be achieved, however, for the described rotational technique overdoses up to more than 20% in small regions seem unavoidable.

This planning study was performed to compare stereotactic linac based radiosurgery of Arteriovenous Malformations (AVM) with current Helical Tomotherapy (HT) and future HT techniques. For 10 patients with AVM, dose distributions and treatment times of “regular” HT delivery (Reg 2.5/1/0.6 cm field width), Running-Start-Stop Treatment (RSS 5/2.5 cm), Axial Mode (Axial 5 cm) and Dynamic Jaw/Dynamic Couch delivery with a maximum field width of 5 cm (DJDC 5) were analysed and compared to linac-based stereotactic radiosurgery. Axial produced the fastest treatment (Axial 4:47 min vs. Linac 32:42 min) at the cost of large brain exposure (V10% 289 ml). Except for Reg 0.6, all other HT techniques achieved significantly shorter treatment times than linac-based treatment ( e.g. Reg 1, 19:42 min, DJDC 6:30 min). However, high-dose brain exposure (V60%) was higher in all HT plans ( e.g. Reg 0.6, 10 ml, Linac 9 ml), and only Reg 0.6 showed better low-dose exposure (V10% of 167 ml vs. 199 ml, not significant). Neither current nor future HT modes in their current version outperformed linac-based stereotactic radiosurgery. However, AVM with special geometry might still benefit from HT.

Among the metastasis patterns of head and neck squamous cell carcinoma (HNSCC), intracranial spread is a rare but dreaded event. To date only very few cases have been reported and clinical and molecular data are sparse. We screened our archives for HNSCC patients from 1992 to 2005 who were diagnosed with brain metastases (BM). For retrospective analysis, all clinico-pathological data including disease-free survival (DFS), local progression-free survival (LPFS), and overall survival (OS) were compiled. Additionally, we assessed the mutational status of the TP53 gene and the prevalence of HPV serotypes by PCR and Sanger sequencing. Immunohistochemistry was applied to detect p16INK4A expression levels as surrogate marker for HPV infection. The prevalence rate of BM in our cohort comprising 193 patients with advanced HNSCC was 5.7 %. Of 11 patients with BM, 3 were female and 9 were male. Seven of the primary tumors were of oropharyngeal origin (OPSCC). LPFS of the cohort was 11.8 months, DFS was 12.1 months and OS was 36.0 months. After the diagnosis of BM, survival was 10.5 months. Five tumors showed a mutation in the TP53 gene, while five of the seven OPSCC tumors had a positive HPV status displaying infection with serotype 16 in all cases. Compared with patients who harbored TP53wt/HPV-positive tumors, patients with TP53 mutations showed a poor prognosis. Compared with the whole cohort, the interval between diagnosis of the primary and the detection of BM was prolonged in the HPV-infected OPSCC subgroup (26.4 vs. 45.6 months). The prognosis of HNSCC patients with BM is poor. In our cohort, most tumors were OPSCC with the majority being HPV positive. Our study points toward a putatively unusual metastatic behavior of HPV-positive OPSCC.

Standard treatment is surgery with stage dependent postoperative radio(chemo)therapy, however, for organ preservation preoperative radio(chemo)therapy is used as an individual approach. The present analysis was performed to access outcome and toxicity of radiotherapeutical treatment of squamous cell carcinoma of the tongue.Sixty-six patients (median age 55 years) with cancer of the mobile tongue (n=30) or tongue margins (n=36) treated between 1982 and 2006 were retrospectively analyzed. Treatment consisted of definitive- (n=13, median dose 66 Gy), adjuvant- (n=31, median dose 60 Gy) or neoadjuvant radiotherapy (n=22, median dose 40 Gy) and chemotherapy (n=34) or immunotherapy (n=1).After a median follow-up of 29 months the three- and five-year overall survival (OS) rates were 59% and 46%, respectively. The median OS was 54 months. Forty-two patients achieved complete remission whereas 14 patients showed partial remission. The one- and two-year loco-regional progression-free survival (LRPFS) rates were 76% and 58%, respectively. The median LRPFS time was 36 months. In χ(2)-test, T-stage showed a trend towards impact on local recurrence (Pearson, p=0.082). In multivariate analysis, alcohol consumption (p=0.003) and gender (p=0.031) were prognostic. Grade III/IV acute toxicity was seen in 52% of patients. None of the locally controlled patients reported grade IV or higher late toxicity.No statistically significant differences between treatment modalities were found, but one should keep in mind that organ preservation plays a major role for quality of life. None of the locally controlled patients reported grade IV or higher late toxicity. However, tumor recurrence is common, especially in advanced tumor stage. Interdisciplinary concepts, further increasing the chance of tumor control are warranted.

Background Aim was to access outcome and toxicity of repeated linac-based radiosurgery in incompletely obliterated cerebral AVM. Patients and methods Between 1998 and 2008, 11 patients were treated with repeated radiosurgery. The median dose to the 80%-isodose was 15 Gy (range, 12–18 Gy). During initial radiosurgery the median dose was 18 Gy (range, 9–22 Gy). Results The median time interval between initial radiosurgery and re-treatment was 9 years (range, 4–16 years). The median follow-up was 26 months (range, 2–115 months). Treatment response was seen in 8 patients (89%). Complete (partial) obliteration was achieved in 5 (3) patients (56%, 33%, respectively).The median time to complete obliteration was 26 months (range, 5–45 months). Pre-existing neurological symptoms improved in 2 patients (18%), were stable in 7 patients (64%) and worsened in 2 patients (18%). Prevalence of intracranial hemorrhage was 9% (1/11). Post-re-treatment intracranial hemorrhage rate was 2.7% (1/38 years at risk). During follow-up, no secondary malignancies or toxicity > grade III were observed. Conclusion Repeated linac-based radiosurgery in incompletely obliterated cerebral AVM is an effective treatment option with a high rate of treatment response and an acceptable risk for side effects. Marginal doses above 15 Gy might further improve the rate of complete obliterations.

BACKGROUND: The purpose of this study was to present planning, feasibility, toxicity, and outcome of helical tomotherapy for spinal cord-sparing reirradiation of spinal metastases and tumors. METHODS: Thirty-six patients with spinal metastases and tumors who had undergone previous radiotherapy were reirradiated with helical tomotherapy because of tumor progression, pain, or compromised stability. Mean spinal cord dose of previous radiotherapy was 36.3 grays (Gy) after a median time interval of 17.5 months. Mean prescribed dose of reirradiation was 34.8 Gy. Daily megavoltage computed tomography (CT) image guidance was performed to assure precise dose application. RESULTS: Mean beam time was 8.4 minutes; the dose maximum to the spinal cord at reirradiation could be limited to a 9.8-Gy median dose (minimum, 5.2 Gy; maximum, 21.8 Gy). Significant pain relief from a median value of 7 on the visual analogue scale before therapy to a median value of 3 at 6 weeks after radiotherapy was achieved. One- and 2-year local control was 76% and 63%; overall survival was 67% after 1 year and 58% after 2 years. One grade 2 skin toxicity and no grade 3 or higher toxicities were observed. CONCLUSIONS: Helical tomotherapy makes reirradiation of spinal metastases and excellent avoidance of the spinal cord possible and achieves good pain relief and local control. With a minimal distance of several millimeters between target volume and spinal cord, tailor-made dose distributions with steep dose gradients around previously irradiated tissue are obtained and precisely applied with daily megavoltage CT-based image guidance. Cancer 2010. © 2010 American Cancer Society.

To investigate whether a new multileaf collimator with a leaf width of 5 mm (MLC-5) over the entire field size of 40 × 40 cm2 improves plan quality compared to a leaf width of 10 mm (MLC-10) in intensity-modulated radiotherapy (IMRT) with integrated boost for head and neck cancer. A plan comparison was performed for ten patients with head and neck cancer. For each patient, seven plans were calculated: one plan with MLC-10 and nine beams, four plans with MLC-5 and nine beams (with different intensity levels and two-dimensional median filter sizes [2D-MFS]), and one seven-beam plan with MLC-5 and MLC-10, respectively. Isocenter, beam angles and planning constraints were not changed. Mean values of common plan parameters over all ten patients were estimated, and plan groups of MLC-5 and MLC-10 with nine and seven beams were compared. The use of MLC-5 led to a significantly higher conformity index and an improvement of the 90% coverage of PTV1 (planning target volume) and PTV2 compared with MLC-10. This was noted in the nine- and seven-beam plans. Within the nine-beam group with MLC-5, a reduction of the segment number by up to 25% at reduced intensity levels and for increased 2D-MFS did not markedly worsen plan quality. Interestingly, a seven-beam IMRT with MLC-5 was inferior to a nine-beam IMRT with MLC-5, but superior to a nine-beam IMRT with MLC-10. The use of an MLC-5 has significant advantages over an MLC-10 with respect to target coverage and protection of normal tissues in step-and-shoot IMRT of head and neck cancer.

Background To retrospectively access outcome and prognostic parameters of linear accelerator-based stereotactic radiosurgery in brain metastases from malignant melanoma. Methods Between 1990 and 2011 140 brain metastases in 84 patients with malignant melanoma (median age 56 years) were treated with stereotactic radiosurgery. At initial stereotactic radiosurgery 48 % of patients showed extracerebral control. The median count of brain metastases in a single patient was 1, the median diameter was 12 mm. The median dose applied was 20 Gy/80 % isodose enclosing. Results The median follow-up was 7 months and the median overall survival 9 months. The 6-, 12- and 24 month overall survival rates were 71 %, 39 % and 25 % respectively. Cerebral follow-up imaging showed complete remission in 20 brain metastases, partial remission in 39 brain metastases, stable disease in 54 brain metastases, progressive disease in 24 brain metastases and pseudo-progression in 3 brain metastases. Median intracerebral control was 5.3 months and the 6- and 12-month intracerebral progression-free survival rates 48 % and 38 %, respectively. Upon univariate analysis, extracerebral control (log-rank, p Conclusion Stereotactic radiosurgery is a well-tolerated and effective treatment option for brain metastases in malignant melanoma and was able to achieve local remissions in several cases. Furthermore, especially patients with controlled extracerebral disease and a low count of brain metastases seem to benefit from this treatment modality. Prospective trials analysing the effects of combined stereotactic radiosurgery and new systemic agents are warranted.

Hadron therapy has already proven to be successful in cancer therapy, and might be a noninvasive alternative for the ablation of cardiac arrhythmias in humans. We present a pilot experiment investigating acute effects of a 12C irradiation on the AV nodes of porcine hearts in a Langendorff setup. This setup was adapted to the requirements of charged particle therapy. Treatment plans were computed on calibrated CTs of the hearts. Irradiation was applied in units of 5 and 10 Gy over a period of about 3 h until a total dose of up to 160 Gy was reached. Repeated application of the same irradiation field helped to mitigate motion artifacts in the resulting dose distribution. After irradiation, PET scans were performed to verify accurate dose application. Acute AV blocks were identified. No other acute effects were observed. Hearts were kept in sinus rhythm for up to 6 h in the Langendorff setup. We demonstrated that 12C ions can be used to select a small target in the heart and, thereby, influence the electrical conduction system. Second, our pilot study seems to suggest that no adverse effects have to be expected immediately during heavy ion irradiation in performing subsequent experiments with doses of 30-60 Gy and intact pigs.

Background: Goal of this retrospective analysis was to evaluate the role of repeat whole brain radiotherapy in the palliative care of patients with brain metastases due to solid tumors. Methods: Data regarding demographic data, primary tumor, metastasis, radiotherapy and symptoms were compiled on 134 patients with cerebral metastases that received repeat whole brain radiotherapy (WBRT) in our clinic between 2002 and 2011. Results: The analyzed group consisted of 63 (47%) women and 71 (53%) men with a median age of 57 at the start of re-irradiation. Most frequent primary site was the lung (87%). Sixty patients with lung cancer received the first WBRT prophylactically. At the time of re-WBRT 81% of all patients suffered from additional extracerebral metastases. Time between first and second WBRT was a median of 13.4 months. Full dose for the first WBRT was 30 Gy in 2.0 Gy single dose, for the second 20 Gy in 2.0 Gy single dose. At the start of the Re-WBRT 81 patients (60.4%) had mild, 32 (23.9%) severe neurological symptoms, 21 patients (15.7%) were asymptomatic. The median Karnofsky performance status was 70%. Overall, re-WBRT was tolerated satisfactorily. Main side effects were fatigue, erythema and focal alopecia, 10% of patients discontinued treatment before reaching the planned dose. Median survival was 2.8 months since the end of the re-WBRT with good performance status at the start of the re-irradiation being a key indicator for longer survival. Fifty-two patients (39%) showed a clinical improvement of neurological symptoms after the therapy, 59 patients (44%) remained stable, 23 patients (17%) showed worse symptoms. Conclusions: From this large patient collective we were able to show that re-WBRT can be an important therapeutic option with low rate of acute side effects for patients in adequate general condition.

Background Patients with malignant melanoma may develop brain metastases during the course of the disease, requiring radiotherapeutic treatment. In patients with 1–3 brain metastases, radiosurgery has been established as a treatment option besides surgery. For patients with 4 or more brain metastases, whole brain radiotherapy is considered the standard treatment. In certain patients with brain metastases, radiation treatment using whole brain helical Tomotherapy with integrated boost and hippocampal-sparing may improve prognosis of these patients. Methods/Design The present prospective, randomized two-armed trial aims to exploratory investigate the treatment response to conventional whole brain radiotherapy applying 30 Gy in 10 fractions versus whole brain helical Tomotherapy applying 30 Gy in 10 fractions with an integrated boost of 50 Gy to the brain metastases as well as hippocampal-sparing in patients with brain metastases from malignant melanoma. The main inclusion criteria include magnetic resonance imaging confirmed brain metastases from a histopathologically confirmed malignant melanoma in patients with a minimum age of 18 years. The main exclusion criteria include a previous radiotherapy of the brain and not having recovered from acute high-grade toxicities of prior therapies. The primary endpoint is treatment-related toxicity. Secondary endpoints include imaging response, local and loco-regional progression-free survival, overall survival and quality of life. Trial registration http://www.drks.de Trial ID: DRKS00005127

Background To retrospectively access outcome and toxicity of whole brain radiotherapy (WBRT) in patients with multiple brain metastases (BM) from malignant melanoma (MM). Patients and methods Results of 87 patients (median age 58 years; 35 female, 52 male) treated by WBRT for BM of MM between 2000 and 2011 were reviewed. Total dose applied was either 30 Gy in 10 fractions (n = 56) or 40 Gy in 20 fractions (n = 31). All but 9 patients suffered from extra-cerebral metastases. Prior surgical resection of BM was performed in 18 patients, salvage stereotactic radiosurgery in 13 patients. Results Mean follow-up was 8 months (range, 0–57 months), the 6- and 12-months overall-(OS) survival rates were 29.2% and 16.5%, respectively. The median OS was 3.5 months. In cerebral follow-up imaging 6 (11) patients showed a complete (partial) remission, while 11 (17) patients had stable disease (intra-cerebral tumor progression). In comparison of total dose, the group treated with 40 Gy in 20 fractions achieved a significant longer OS (p = 0.003, median 3.1 vs. 5.6 months). Furthermore, DS-GPA score (p Conclusion Treatment of BM from MM with WBRT is tolerated well and some remissions of BM could be achieved. An advantage for higher treatment total doses was seen. However, outcome is non-satisfying, and further improvements in treatment of BM from MM are warranted.

Background To retrospectively access the outcome and toxicity of a total skin electron beam therapy (TSEBT) in patients with cutaneous lymphoma (CL) or leukemia. Patients and methods Treatment results of 25 patients (median age 63 years; 5 female, 20 male) with cutaneous manifestations of advanced and therapy-refractory CL (n = 21; T-cell lymphomas n = 18, B-cell lymphomas n = 3) stage IIB-IV or leukemia (n = 4; AML n = 2, CLL n = 1, PDC n = 1) treated between 1993 and 2010 were reviewed. All patients were symptomatic. The median total dose was 29Gy, applied in 29 fractions of median 1 Gy each. Results The median follow-up was 10 months. Palliation was achieved in 23 patients (92%). A clinical complete response was documented in 13 (52%) and a partial response in 10 patients (40%). The median time to skin progression was 5 months (range 1–18 months) and the actuarial one-year progression-free survival 35%. The median overall survival (OS) after the initiation of TSEBT was 10 months (range 1–46 months) and the actuarial one-year OS 45%. TSEBT related acute adverse events (grade 1 or 2) were observed in all patients during the treatment period. An acute grade 3 epitheliolysis developed in eight patients (32%). Long-term adverse events as a hyperpigmentation of the skin (grade 1 or 2) were documented in 19 patients (76%), and a hypohidrosis in seven patients (28%). Conclusion For palliation of symptomatic cutaneous manifestations of advanced cutaneous lymphoma or leukemia, total skin electron beam therapy is an efficient and well tolerated considerable treatment option.

Background To retrospectively assess feasibility and toxicity of proton therapy in patients with low-grade glioma (WHO °I/II). Patients and methods Proton beam therapy only administered in 19 patients (median age 29 years; 9 female, 10 male) for low-grade glioma between 2010 and 2011 was reviewed. In 6 cases proton therapy was performed due to tumor progression after biopsy, in 8 cases each due to tumor progression after (partial-) resection, and in 5 cases due to tumor progression after chemotherapy. Median total dose applied was 54 GyE (range, 48,6-54 GyE) in single fractions of median 1.8 GyE. Median clinical target volume was 99 cc (range, 6–463 cc) and treated using median 2 beams (range, 1–2). Results Proton therapy was finished as planned in all cases. At end of proton therapy, 13 patients showed focal alopecia, 6 patients reported mild fatigue, one patient with temporal tumor localization concentration deficits and speech errors and one more patient deficits in short-term memory. Four patients did not report any side effects. During follow-up, one patient presented with pseudo-progression showing worsening of general condition and brain edema 1–2 months after last irradiation and restitution after 6 months. In the present MR imaging (median follow-up 5 months; range 0–22 months) 12 patients had stable disease, 2 (1) patients partial (complete) remission, one more patient pseudo-progression (differential diagnosis: tumor progression) 4 weeks after irradiation without having had further follow-up imaging so far, and one patient tumor progression approximately 9 months after irradiation. Conclusion Regarding early side effects, mild alopecia was the predominant finding. The rate of alopecia seems to be due to large treatment volumes as well as the anatomical locations of the target volumes and might be avoided by using multiple beams and the gantry in the future. Further evaluations including neuropsychological testing are in preparation.

Purpose We retrospectively evaluated the outcome and toxicity of external beam radiotherapy (EBRT) after airway stents were placed in patients treated for malignant airway obstruction. Methods and Materials Between 2004 and 2009, we performed airway stenting followed by EBRT in 43 patients for symptomatic primary lung cancer ( n = 31) or other thoracic malignancies ( n = 12). The median time interval between stent placement and first irradiation was 14 days. A median total dose of 50 Gy was delivered. Sixty-seven percent of the patients had reduced performance status (Karnofsky performance score, ≤70). Results EBRT had to be stopped prematurely in 16 patients (37%), at a median total dose of 17 Gy, for various reasons. In this group of patients, the survival was poor, with a median overall survival (OS) of only 21 days. Twenty-seven patients (63%) completed radiotherapy as planned, with a median OS of 8.4 months. Fourteen of 43 patients (33%) developed at least one Common Terminology Criteria for Adverse Event of grade 3 to 5. The most common event was a malignant restenosis of the stent leading to asphyxia ( n = 7), followed by fistula formation ( n = 4), necrosis ( n = 3), mediastinitis with abscess ( n = 1), secondary nonmalignant airway stenosis ( n = 1), and hemoptysis ( n = 1). With the exception of one event, all events were associated with a local progression of the tumor. Conclusions Although the long-term prognosis for patients with malignant airway obstruction is poor, airway stenting combined with EBRT offers a possible therapeutic option, achieving fast relief of acute respiratory distress with an associated antitumor effect, resulting in a potential survival benefit. However, due to local advanced tumor growth, increased rates of adverse events are to be expected, necessitating careful monitoring.

Background. In this retrospective investigation we analyzed outcome and toxicity after intensity-modulated reirradiation of recurrent head and neck cancer. Methods. Thirty-eight patients with local recurrent head and neck cancer were evaluated. The median dose of initial radiother- apy was 61 Gy. Reirradiation was carried out with step-and-shoot intensity-modulated radiotherapy (median dose: 49 Gy). Results. Median overall survival was 17 months, and the 1- and 2-year overall survival rates were 63% and 34%. The 1- and 2-year local control rates were 57% and 53%. Distant spread occurred in 34%, and reirradiation induced consider- able late toxicity in 21% of the patients. Thirty-two percent showed increased xerostomia after reirradiation. The risk for xerostomia was significantly higher for cumulative mean doses of � 45 Gy to parotid glands. Considering median cumulative maximum doses of 53 Gy to the spinal cord and 63 Gy to the brainstem, no late toxicities were observed. Conclusions. Reirradiation with intensity-modulated radio- therapy in recurrent head and neck cancer is feasible with ac- ceptable toxicity and yields encouraging rates of local control and overall survival. V C 2011 Wiley Periodicals, Inc. Head Neck 33: 1695-1702, 2011

Purpose To investigate the next generation of helical tomotherapy delivery with dynamic jaw and dynamic couch movements. Methods and Materials The new technique of dynamic jaw and dynamic couch movements is described, and a comparative planning study is performed. Ten nasopharyngeal cancer patients with skull base infiltration were chosen for this comparison of longitudinal dose profiles using regular tomotherapy delivery, running-start-stop treatment, and dynamic jaw and dynamic couch delivery. A multifocal simultaneous integrated boost concept was used (70.4Gy to the primary tumor and involved lymph nodes; 57.4Gy to the bilateral cervical lymphatic drainage pathways, 32 fractions). Target coverage, conformity, homogeneity, sparing of organs at risk, integral dose, and radiation delivery time were evaluated. Results Mean parotid dose for all different deliveries was between 24.8 and 26.1Gy, without significant differences. The mean integral dose was lowered by 6.3% by using the dynamic technique, in comparison with a 2.5-cm-field width for regular delivery and 16.7% with 5-cm-field width for regular delivery. Dynamic jaw and couch movements reduced the calculated radiation time by 66% of the time required with regular 2.5-cm-field width delivery (199 sec vs. 595 sec, p Conclusions The current delivery mode of helical tomotherapy produces dose distributions with conformal avoidance of parotid glands, brain stem, and spinal cord. The new technology with dynamic jaw and couch movements improves the plan quality by reducing the dose penumbra and thereby reducing the integral dose. In addition, radiation time is reduced by 66% of the regular delivery time.

Purpose This study's aim was to assess outcome and toxicity of high-dose-rate endoluminal brachytherapy (HDREB) for recurrent bronchial carcinoma. Methods and Materials From 1987 to 2005, 41 patients were treated with HDREB for symptomatic recurrent bronchial carcinoma. All patients had previously undergone external beam radiotherapy (EBRT) with a median dose of 56 Gy (range, 30–70 Gy). The median HDREB dose applied was 15 Gy (range, 5–29 Gy). The median time interval between primary EBRT and reirradiation was 9 months (range, 2–54 months). Results After a median follow-up of 6.7 months, the 6-, 12-, and 24-month overall survival rates were 58%, 18%, and 7%, respectively. The median overall survival time was 6.7 months. Local remission was achieved in 73% of patients ( n = 30). A total of 24% of patients ( n = 10) showed no response or progressive disease within 8 weeks after treatment. In 1 patient, treatment response was not documented. The 6-, 12-, and 24-month local control rates were 38%, 17%, and 3%, respectively. The median local progression-free survival time was 4 months (range, 1–23 months). Prognostic factors were a total dose of ≥15 Gy of HDREB ( p = 0.029) and a Karnofsky performance score of ≥80% ( p = 0.0012). The cause of death was locoregional progression in 27% of patients ( n = 11), distant metastases in 24% of patients ( n = 10), fatal hemorrhage in 15% of patients ( n = 6), and other causes in 29% of patients ( n = 12). None of the patients with locally controlled disease showed grade 3 or 4 late effects. Conclusions Palliative treatment of symptomatic, locally recurrent bronchial carcinoma with HDREB can effectively relieve symptoms in the majority of patients while causing only few complications. Still, time to progression is short.

To investigate the influence of local density increase by i.v. contrast agent on dose calculation in linac-based radiosurgery (RS) of cerebral arteriovenous malformations (AVMs).RS was performed after three-dimensional (3-D) treatment planning using a total number of nine to 14 beams. Mean target volume was 5.3 cm(3) (range, 0.1-41.2 cm(3)). Mean maximum diameter was 23.2 mm (range, 8-51 mm). Dose deviation was estimated and calculated from the enhanced and unenhanced datasets of 30 patients. Dose calculation was performed using the same RS treatment plan on both datasets. Both plans were standardized to 1 Gy at isocenter with the same dose weight for all beams.Mean difference of Hounsfield units (DeltaHU) between enhanced and unenhanced CT was 152 HU (range, 50-350 HU). The estimated dose deviation wasor= 1% in 80% of cases with a mean deviation of 0.67% and a maximum dose deviation of 1.8%. With increasing DeltaHU and increasing maximum diameter dose deviation increased as well. The calculated overdosage in ten datasets of enhanced and unenhanced CT scans was 0.66% mean (range, 0.2-1.2%).The use of i.v. contrast agent in 3-D treatment planning for RS of cerebral AVMs may lead to an underestimation of actual applied dose. The effect on dose calculation is rather low with dose deviations+1% in most of the cases. However, there are cases especially in large AVMs with high DeltaHU located next to critical, radiosensitive structures in which an additional unenhanced CT scan is recommended for exact dose calculation to avoid side effects.

To assess long-term toxicity, outcome and prognostic factors after multimodal treatment of cervical lymph node metastases from cancer of unknown primary (CUP). In a retrospective study, the treatment results of 84 patients with CUP (median age 63 years, N1 n = 0, N2 n = 44, N3 n = 39, Nx n = 1), treated between 1971 and 2002 with radiotherapy (n = 84, median dose 60 Gy), platinum-based chemotherapy (n = 23) and surgery (n = 69, tonsillectomy [n = 40], neck dissection [n = 52], suprahyoid dissection [n = 18], lymph node excision [n = 14]), were analyzed. After a mean follow-up time of 25 months (ranging from 0.1 to 260 months), the 3- and 5-year overall (disease-free) survival rates were 30% (39%) and 27% (34%), respectively. 75% of individuals achieved remission, whereas 23% showed no change or progression after treatment. The 3-, 5- and 10-year local control rates were 58%, 58% and 46%, respectively. 40% of patients suffered grade 3/4 late toxicity: severe skin contracture/induration (n = 2) and severe xerostomia (n = 32). Tonsillectomy (p = 0.003) and neck dissection (p = 0.037) performed before radiotherapy significantly improved outcome. Other prognostic factors were age (p = 0.0235), extracapsular spread (n = 63; p = 0.0045), incomplete resection (n = 24; p = 0.0026), nodal disease (p = 0.0034), and distant metastases (n = 17; p = 0.0002). After multivariate analysis only extracapsular spread (p = 0.004) and tonsillectomy (p = 0.01) showed impact on survival. Irradiation of cervical lymph node metastases from CUP is an effective treatment option with acceptable late toxicity. Complete tonsillectomy and neck dissection significantly improved survival in N2/N3 disease. Extracapsular spread was the best predictor for survival and local control. Prospective studies defining a standard treatment are needed.

Purpose To access the long-time outcome and patterns of failure in patients with advanced head and neck squamous cell carcinoma (HNSCC). Methods and materials Between 1992 and 2005 127 patients (median age 55 years, UICC stage III n = 6, stage IV n = 121) with primarily inoperable, advanced HNSCC were treated with definite platinum-based radiochemotherapy (median dose 66.4 Gy). Analysed end-points were overall survival (OS), disease-free survival (DFS), loco-regional progression-free survival (LPFS), development of distant metastases (DM), prognostic factors and causes of death. Results The mean follow-up time was 34 months (range, 3-156 months), the 3-, 5- and 10-year OS rates were 39%, 28% and 14%, respectively. The median OS was 23 months. Forty-seven patients achieved a complete remission and 78 patients a partial remission. The median LPFS was 17 months, the 3-, 5- and 10-year LPFS rates were 41%, 33% and 30%, respectively. The LPFS was dependent on the nodal stage (p = 0.029). The median DFS was 11 months (range, 2-156 months), the 3-, 5- and 10-year DFS rates were 30%, 24% and 22%, respectively. Prognostic factors in univariate analyses were alcohol abuse (n = 102, p = 0.015), complete remission (n = 47, p < 0.001), local recurrence (n = 71, p < 0.001), development of DM (n = 45, p < 0.001; median OS 16 months) and borderline significance in nodal stage N2 versus N3 (p = 0.06). Median OS was 26 months with lung metastases (n = 17). Nodal stage was a predictive factor for the development of DM (p = 0.025). Cause of death was most commonly tumor progression. Conclusions In stage IV HNSCC long-term survival is rare and DM is a significant predictor for mortality. If patients developed DM, lung metastases had the most favourable prognosis, so intensified palliative treatment might be justified in DM limited to the lungs.