Background and purposeCombined photon intensity-modulated radiotherapy (IMRT) and sequential dose-escalated carbon ion beam therapy (IBT) is a technically advanced treatment option for head and neck malignancies. We proposed and evaluated an integrated planning strategy as opposed to an established and largely separated planning workflow.Materials and methodsTen patients with representative malignancies of the head and neck region underwent combined carbon-photon radiotherapy (RT) in our facilities. Clinical plans were created according to the separated workflow with independent optimization stages for both modalities. Experimental plans incorporated the existing carbon IBT dose distribution into the optimization stage of a step-and-shoot photon IMRT (bias dose planning).ResultsCumulative dose distributions showed statistically significant differences between the two planning strategies and were predominantly in favor of the integrated approach. As such, target irradiation was generally maintained or even improved in a subset of metrics, while normal tissue sparing was widely enhanced; for instance, in the ipsilateral temporal lobe with median Dmean of −16% (p < 0.001). Maximum doses D1% (with adjustment for different fractionation) fell below thresholds for toxicity risk in a minority of instances, where they were previously exceeded. Integral dose did not differ significantly.ConclusionsOur findings indicate that combination planning of carbon-photon RT for head and neck malignancies may benefit from a proposed bias dose method, yielding favorable dose distribution characteristics and a streamlined planning workflow with fewer plan revisions. Further research is necessary to validate these observations in terms of robustness and their potential for higher tumor control.

Background: Leptomeningeal carcinomatosis (LC) is a severe complication of metastatic tumor spread to the central nervous system. Prognosis is dismal with a median overall survival (OS) of similar to 10-15 weeks. Treatment options include radiotherapy (RT) to involved sites, systemic chemo- or targeted therapy, intrathecal chemotherapy and best supportive care with dexamethasone. Craniospinal irradiation (CSI) is a more aggressive radiotherapeutic approach, for which very limited data exists. Here, we report on our 10-year experience with palliative CSI of selected patients with LC. Patients and methods: Twenty-five patients received CSI for the treatment of LC at our institution between 2008 and 2018. Patients were selected individually for CSI based on clinical performance, presenting symptoms and estimated benefit. Median patient age was 53 years (IQR: 45-59), and breast cancer was the most common primary. Additional brain metastases were found in 18 patients (72.0%). RT was delivered at a TomoTherapy machine, using helical intensity-modulated radiotherapy (IMRT). The most commonly prescribed dose was 36 Gy in 20 fractions, corresponding to a median biologically equivalent dose of 40.8 Gy (IQR: 39.0-2.5). Clinical performance and neurologic function were assessed before and in response to therapy, and deficits were retrospectively quantified on the 5-point neurologic function scale (NFS). A Cox proportional hazards model with univariate and multivariate analyses was fitted for survival. Results: Twenty-one patients died and four were alive at the time of analysis. Median OS from LC diagnosis was 19.3 weeks (IQR: 9.3-34.0, 95% CI: 11.0-32.0). In univariate analysis, a Karnofsky performance scale index (KPI) >= 70% (P=0.001), age <= 55 years at LC diagnosis (P=0.022), cerebrospinal fluid (CSF) protein <100 mg/dL (P=0.018) and no more than mild or moderate neurologic deficits (NFS <= 2; P=0.007) were predictive of longer OS. So were the neurologic response to treatment (P=0.018) and the application of systemic therapy after RT completion (P=0.029). The presence of CSF flow obstruction was predictive of shorter OS (P=0.026). In multivariate analysis, age at LC diagnosis (P=0.018), KPI (P<0.001) and neurologic response (P=0.037) remained as independent prognostic factors for longer OS. Treatment-associated toxicity was manageable and mostly grades I and II according to the Common Terminology Criteria for Adverse Events v4.0. Eight patients (32%) developed grade III myelosuppression. Neurologic symptom stabilization could be achieved in 40.0% and a sizeable improvement in 28.0% of all patients. Conclusion: CSI for the treatment of LC is feasible and may have therapeutic value in carefully selected patients, alleviating symptoms or delaying neurologic deterioration. OS after CSI was comparable to the rates described in current literature for patients with LC. The use of modern irradiation techniques such as helical IMRT is warranted to limit toxicity. Patient selection should take into account prognostic factors such as age, clinical performance, neurologic function and the availability of systemic treatment options.

Background and purpose: Radiosensitizers and heavy ion irradiation could improve therapy for female patients with malignant tumors located in the pelvic region through dose reduction. Aim of the study was to investigate the radiosensitizing potential of 2-deoxy-D-glucose (2-DG) in combination with carbon ion-irradiation (C-12) in representative cell lines of cancer in the female pelvic region. Materials and methods: The human cervix carcinoma cell line CaSki and the colorectal carcinoma cell line WiDr were used. 2-DG was employed in two different settings, pretreatment and treatment simultaneous to irradiation. Clonogenic survival, alpha and beta values for application of the linear quadratic model and relative biological effectiveness (RBE) were determined. ANOVA tests were used for statistical group comparison. Isobolograms were generated for curve comparisons. Results: The comparison of monotherapy with C-12 versus photons yielded RBE values of 2.4 for CaSki and 3.5 for WiDr along with a significant increase of a values in the C-12 setting. 2-DG monotherapy reduced the colony formation of both cell lines. Radiosensitization was found in WiDr for the combination of photon irradiation with synchronous application of 2-DG. The same setup for C-12 showed no radiosensitization, but rather an additive effect. In all settings with CaSki, the combination of irradiation and 2-DG exhibited additive properties. Conclusion: The combination of 2-DG and photon therapy, as well as irradiation with carbon ions can overcome radioresistance of tumor cells such as WiDr. (C) 2019 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.

Introduction: This prospective, non-randomized phase II trial aimed to investigate the role of additional irradiation of the pelvic nodes for patients with prostate cancer and a high risk for nodal metastases using helical intensity-modulated radiotherapy with daily image guidance (IMRT/IGRT). Methods and materials: Between 2009 and 2012, 40 men with treatment-naïve prostate cancer and a risk of lymph node involvement of more than 20% were enrolled in the PLATIN-1 trial. All patients received definitive, helical IMRT of the pelvic nodes (total dose of 51.0 Gy) with a simultaneous integrated boost (SIB) to the prostate (total dose of 76.5 Gy) in 34 fractions. Antihormonal therapy (AHT) was administered for a minimum of 2 months before radiotherapy continuing for at least 24 months. Results: After a median follow-up of 71 months (range: 5-95 months), pelvic irradiation was associated with a 5-year overall survival (OS) and biochemical progression-free survival (bPFS) of 94.3% and 83.6%, respectively. For our cohort, no grade 4 gastrointestinal (GI) and genitourinary (GU) toxicity was observed. Quality of life (QoL) assessed by EORTC QLQ-C30 questionnaire was comparable to EORTC reference values without significant changes. Conclusion: The current trial demonstrates that elective IMRT/IGRT of the pelvic nodes with SIB to the prostate for patients with a high-risk of lymphatic spread is safe and shows an excellent clinical outcome without compromising the quality of life. The PLATIN-1 trial delivers eminent baseline data for future studies using modern irradiation techniques.

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/AIM:Carbon ion radiotherapy (CIRT) offers high conformality and ability to dose-escalate skull base chordomas, with promising clinical data. However, it is an imperative measure to economically justify the use of such high-priced new technologies. Herein, we investigated the cost-effectiveness of CIRT compared to photon radiotherapy (PRT) using 10-year outcome data extrapolated to a 34-year time frame.MATERIALS AND METHODS:Data regarding costs of PRT, as well as 10-year outcomes were obtained from published sources. Corresponding figures for CIRT were acquired from institutional and published sources. Adjustment was made in order to compare both cost figures, including elimination of additional financing and follow-up, so that only direct costs of treatment and the cost of progression were compared between both modalities. The incremental cost-effectiveness ratio (ICER) was calculated as the difference in cost between both modalities divided by the difference in 34-year quality-adjusted life-year (QALY) outcomes. The annual gross domestic product per capita cost-effectiveness threshold definition (as recommended by the WHO) was employed.RESULTS:The total cost of a complete course of CIRT (20-22 fractions) was €31,538.21. After removal of financing and follow-up costs, the adjusted direct cost of CIRT utilized for comparison was €18,957.78. In a previous publication, the cost of PRT was €4,700.00. ICERs were based upon these direct cost figures and the average of reported 10-year progression-free survival (PFS) values with PRT (41.1%) and CIRT (54%), as well as gained PFS years (10.66 years CIRT, 8.58 years PRT). QALYs were 6.65 for photon RT and 8.26 for CIRT, a difference of 1.61 discounted lifetime QALYs for patients treated with CIRT. The overall ICER was €8,855.76/QALY. If the cost of progression/recurrence treated with imatinib were included into the calculation, the total ICER was €170.61/QALY.CONCLUSION:CIRT is a highly cost-effective option to treat chordoma.

The present work aimed to analyze the feasibility of a shuttle-based MRI-guided radiation therapy (MRgRT) in the treatment of pelvic malignancies.

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.

We developed a new approach to produce individual immobilization devices for the head based on MRI data and 3D printing technologies. The purpose of this study was to determine positioning accuracy with healthy volunteers. 3D MRI data of the head were acquired for 8 volunteers. In-house developed software processed the image data to generate a surface mesh model of the immobilization mask. After adding an interface for the couch, the fixation setup was materialized using a 3D printer with acrylonitrile butadiene styrene (ABS). Repeated MRI datasets (n=10) were acquired for all volunteers wearing their masks thus simulating a setup for multiple fractions. Using automatic image-to-image registration, displacements of the head were calculated relative to the first dataset (6 degrees of freedom). The production process has been described in detail. The absolute lateral (x), vertical (y) and longitudinal (z) translations ranged between -0.7 and 0.5 mm, -1.8 and 1.4 mm, and -1.6 and 2.4 mm, respectively. The absolute rotations for pitch (x), yaw (y) and roll (z) ranged between -0.9 and 0.8°, -0.5 and 1.1°, and -0.6 and 0.8°, respectively. The mean 3D displacement was 0.9 mm with a standard deviation (SD) of the systematic and random error of 0.2 mm and 0.5 mm, respectively. In conclusion, an almost entirely automated production process of 3D printed immobilization masks for the head derived from MRI data was established. A high level of setup accuracy was demonstrated in a volunteer cohort. Future research will have to focus on workflow optimization and clinical evaluation.

Background Treatment of patients with pelvic adenoid cystic carcinoma (ACC) remains a challenge owing to the rarity of the disease, the lack of data, and the relative radioresistance of these tumors. Case reports This case series presents the results of three patients with recurrent or inoperable pelvic ACC treated with intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost. Patients received C12 therapy at a dose of 3 Gray equivalents (GyE) (relative biological effectiveness [RBE]) per fraction up to 24 GyE RBE, followed by 50 GyE of photon IMRT in 25 fractions. Conclusion IMRT plus C12 ion boost as a definitive or adjuvant treatment for pelvic ACCs seems to be a promising therapeutic option. No unexpected toxicity was detected and the observed toxicity remained consistently low. The initial treatment response is promising and similar to that experienced for head and neck ACCs.

PURPOSE:Leptomeningeal metastasis (LM) is an increasingly common complication of late-stage systemic cancer, for which there is no standard treatment. We analyzed outcome and toxicity in patients with LM undergoing craniospinal irradiation via helical tomotherapy (HT-CSI) at our institution.PATIENTS AND METHODS:The charts of 15 patients diagnosed with LM and undergoing HT-CSI between 2006 and 2014 were retrospectively assessed. Main neoplasms included breast cancer, lung cancer, and lymphoma. All patients presented with cranial neuropathy due to LM. Follow-up was performed regularly. Survival analysis was performed by the Kaplan-Meier method, and prognostic factors were tested using the COX-regression model.RESULTS:Median survival by cancer type was 6 (breast cancer), 1 (lung cancer), and 2 months (lymphoma), respectively. Median overall survival and relapse-free survival were calculated to be between 2 and 3 months. Six- and 12-month survival was 30% (95% CI 0.08-0.5) and 20% (95% CI 0.05-0.4), respectively. Symptom palliation occurred in 53% of patients in general, but in 67% of breast cancer patients, in particular. Patients with lung cancer experienced no improvement. Most common acute treatment-related toxicity at different levels were hematological toxicity, multiple cranial neuropathy, fatigue, infections, nausea, and headache.CONCLUSION:HT-CSI can help meet the challenge of treating patients with LM, especially because it can palliate symptoms and improve neurological functions. One-year survival remains as disappointing as before.

Introduction: We evaluated acute and chronic side effects of 3D conformal radiotherapy (3D-CRT) and intensity-modulated radiation therapy (IMRT) in female patients with anal carcinoma and accessed correlations between dosimetric parameters and the considered toxicities. Methods: For 70 women with anal cancer treated at our department, acute and chronic side effects and quality of life (QoL) were evaluated with questionnaires using the Common Terminology Criteria for Adverse Events (CTCAE v. 4.0.) and Late Effects in Normal Tissue, Subjective, Objective Management and Analytic Scales (LentSoma) before, during, and after the treatment. Results: Forty-seven out of 70 (67%) patients completed the questionnaire and were enrolled in the study. Only poor urinary stream, loss of pubic hair during chemoradiation, and chronic vaginal dryness were observed more frequently in the 3D-CRT group compared to the IMRT group (univariable logistic regression p = .032, p = .04, p = .049, respectively). After the treatment, 43% in the 3D-CRT group and 29% in the IMRT group reported a severe loss of QoL. A higher proportion among the patients receiving a genital V20 ⩾35% showed grade 1–3 side effects such as chronic dyspareunia (p = .035; Fisher exact test). Conclusion: Our results suggest that the use of IMRT decreases acute and chronic adverse effects although reduced QoL also occurred in the IMRT group. These effects are likely to be underreported in retrospective studies using physician-reported outcome measures.

PURPOSE:To investigate the extent of MR image distortions in the pelvis caused by susceptibility-induced field inhomogeneities in MR images in the context of a study on MR-guided radiotherapy.METHODS:Using a high-bandwidth double-echo gradient echo sequence, field maps and distortion maps of the pelvis were calculated and evaluated for 219 exams (92 of female and 127 of male patients) to investigate patient-related image distortions caused by susceptibility differences in an ongoing study on MR-guided radiotherapy. The evaluation of distortions in the regions "rectum", "prostate", "cervix", and in a reference region in the gluteus maximus was based on masks drawn by two readers.RESULTS:Distortions in the prostate and cervix were smaller than 0.03 px (0.1 mm) for 99% of voxels, and reached a maximum value of 0.09 px (0.3 mm). In the reference region, maximum distortions were smaller than in the prostate and cervix.CONCLUSIONS:Using a geometric uncertainty of 0.2 px (0.6 mm) in margin definition for organs that are close to the rectum like the prostate and the cervix would be a cautious choice to account for susceptibility-induced distortions that can arise during MR-based treatment guidance for the imaging setting used in this study. Since distortions are inversely proportional to the readout bandwidth of the sequence, safety margins need to be adapted adequately. Additional sources of image distortions like gradient nonlinearities are not included in our margin recommendations and should be considered separately.

The aim of this study was to describe early and late toxicity, survival and local control in 45 patients with primary brain tumors treated with helical tomotherapy craniospinal irradiation (HT-CSI). From 2006 to 2014, 45 patients with central nervous system malignancies were treated with HT-CSI. The most common tumors were medulloblastoma in 20 patients, ependymoma in 10 patients, intracranial germinoma (ICG) in 7 patients, and primitive neuroectodermal tumor in 4 patients. Hematological toxicity during treatment included leukopenia Grades 1-4 (6.7%, 33.3%, 37.8% and 17.8%, respectively), anemia Grades 1-4 (44.4%, 22.2%, 22.2% and 0%, respectively) and thrombocytopenia Grades 1-4 (51.1%, 15.6%, 15.6% and 6.7%, respectively). The most common acute toxicities were nausea, vomiting, fatigue, loss of appetite, alopecia and neurotoxicity. No Grade 3 or higher late toxicity occurred. The overall 3- and 5-year survival rates were 80% and 70%, respectively. Survival for the main tumor entities included 3- and 5-year survival rates of 80% and 70%, respectively, for patients with medulloblastoma, 70% for both in patients with ependymoma, and 100% for both in patients with ICG. Relapse occurred in 11 patients (24.4%): 10 with local and 1 with multifocal relapse. One patient experienced a secondary cancer. M-status and the results of the re-evaluation at the end of treatment were significantly related to survival. Survival after HT-CSI was in line with the existing literature, and acute treatment-induced toxicity resolved quickly. Compared with conventional radiotherapy, HT offers benefits such as avoiding gaps and junctions, sparing organs, and better and more homogeneous dose distribution and coverage of the target volume.