Individual 3D-printed fixation masks for radiotherapy: first clinical experiences.

PURPOSE: To show the feasibility of 3D-printed fixation masks for whole brain radiation therapy in a clinical setting and perform a first comparison to an established thermoplastic mask system. METHODS: Six patients were irradiated with whole brain radiotherapy using individually 3D-printed masks. Daily image guidance and position correction were performed prior to each irradiation fraction. The vectors of the daily position correction were compared to two collectives of patients, who were irradiated using the standard thermoplastic mask system (one cohort with head masks; one cohort with head and neck masks). RESULTS: The mean systematic errors in the experimental cohort ranged between 0.59 and 2.10 mm which is in a comparable range to the control groups (0.18 mm-0.68 mm and 0.34 mm-2.96 mm, respectively). The 3D-printed masks seem to be an alternative to the established thermoplastic mask systems. Nevertheless, further investigation will need to be performed. CONCLUSION: The prevailing study showed a reliable and reproducible interfractional positioning accuracy using individually 3D-printed masks for whole brain irradiation in a clinical routine. Further investigations, especially concerning smaller target volumes or other areas of the body, need to be performed before using the system on a larger basis.

Exploring MR regression patterns in rectal cancer during neoadjuvant radiochemotherapy with daily T2- and diffusion-weighted MRI.

BACKGROUND: To date, only limited magnetic resonance imaging (MRI) data are available concerning tumor regression during neoadjuvant radiochemotherapy (RCT) of rectal cancer patients, which is a prerequisite for adaptive radiotherapy (RT) concepts. This exploratory study prospectively evaluated daily fractional MRI during neoadjuvant treatment to analyze the predictive value of MR biomarkers for treatment response. METHODS: Locally advanced rectal cancer patients were examined with daily MRI during neoadjuvant RCT. Contouring of the tumor volume was performed for each MRI scan by using T2- and diffusion-weighted-imaging (DWI)-sequences. The daily apparent-diffusion coefficient (ADC) was calculated. Volumetric and functional tumor changes during RCT were analyzed and correlated with the pathological response after surgical resection. RESULTS: In total, 171 MRI scans of eight patients were analyzed regarding anatomical and functional dynamics during RCT. Pathological complete response (pCR) could be achieved in four patients, and four patients had a pathological partial response (pPR) following neoadjuvant treatment. T2- and DWI-based volumetry proved to be statistically significant in terms of therapeutic response, and volumetric thresholds at week two and week four during RCT were defined for the prediction of pCR. In contrast, the average tumor ADC values widely overlapped between both response groups during RCT and appeared inadequate to predict treatment response in our patient cohort. CONCLUSION: This prospective exploratory study supports the hypothesis that MRI may be able to predict pCR of rectal cancers early during neoadjuvant RCT. Our data therefore provide a useful template to tailor future MR-guided adaptive treatment concepts.

Nomogram based overall survival prediction in stereotactic body radiotherapy for oligo-metastatic lung disease.

BACKGROUND: Radical local treatment of pulmonary metastases is practiced with increasing frequency due to acknowledgment and better understanding of oligo-metastatic disease. This study aimed to develop a nomogram predicting overall survival (OS) after stereotactic body radiotherapy (SBRT) for pulmonary metastases. PATIENTS AND METHODS: A multi-institutional database of 670 patients treated with SBRT for pulmonary metastases was used as training cohort. Cox regression analysis with bidirectional variable elimination was performed to identify factors to be included into the nomogram model to predict 2-year OS. The calibration rate of the nomogram was assessed by plotting the actual Kaplan-Meier 2-year OS against the nomogram predicted survival. The nomogram was externally validated using two separate monocentric databases of 145 and 92 patients treated with SBRT for pulmonary metastases. RESULTS: The median follow up of the trainings cohort was 14.3months, the 2-year and 5-year OS was 52.6% and 23.7%, respectively. Karnofsky performance index, type of the primary tumor, control of the primary tumor, maximum diameter of the largest treated metastasis and number of metastases (1 versus >1) were significant prognostic factors in the Cox model (all p<0.05). The calculated concordance-index for the nomogram was 0.73 (concordance indexes of all prognostic factors between 0.54 and 0.6). Based on the nomogram the training cohort was divided into 4 groups and 2-year OS ranged between 24.2% and 76.1% (predicted OS between 30.2% and 78.4%). The nomogram discriminated between risk groups in the two validation cohorts (concordance index 0.68 and 0.67). CONCLUSIONS: A nomogram for prediction of OS after SBRT for pulmonary metastases was generated and externally validated. This tool might be helpful for interdisciplinary discussion and evaluation of local and systemic treatment options in the oligo-metastatic setting. KEY MESSAGE: A nomogram for prediction of overall survival after stereotactic body radiotherapy (SBRT) for pulmonary metastases was developed and externally validated. This tool might be helpful for interdisciplinary discussion and evaluation of local and systemic treatment options in the oligo-metastatic setting.

SBRT for centrally localized NSCLC - What is too central?

PURPOSE: Current guidelines recommend stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer (NSCLC) in medically inoperable patients. There are excellent outcome and toxicity data for SBRT of peripheral lung tumors. However, the discussion on SBRT for centrally located tumors is controversial. This study evaluated current clinical practice regarding SBRT of centrally located lung tumors, to identify common fractionation schedules and commonly accepted contraindications for SBRT. METHODS: A questionnaire consisting of two parts was introduced at the annual meeting of the DEGRO working group on stereotactic radiotherapy, representing centers in Germany and Switzerland. The first part of the questionnaire covered general information about the centers, whereas the second part specifically addressed SBRT of centrally located lung tumors, using case examples of nine primary NSCLC patients. Reconstructions of a contrast enhanced CT, as well as PET-Imaging for each case were demonstrated to the participants. RESULTS: Twenty-six centers participated in the meeting. The majority was academic (73%), participated in interdisciplinary thoracic oncology tumorboards (88%) and offered SBRT for lung tumors (96%). Two centers questioned the indication of SBRT for central lung tumors because of lack of evidence. The majority of centers had experience in SBRT for central lung tumors (88%) and half of the centers reported more than ten cases treated during a median period of five years. Most fractionation schedules used PTV encompassing doses of 48-60 Gy in eight fractions with maximum doses of 125-150%. A clear indication for SBRT treatment was seen by more than 85% of centers in three of the nine patients in whom tumors were small and not closer than 2 cm to the main bronchus. Prior pneumonectomy or immediate adjacency to hilar/mediastinal structures were not considered as contraindications for SBRT. In cases where the tumor exceeded 4 cm in diameter or was located closer than 4 cm to the carina 50-80% of centers saw an indication for SBRT. One case, with a 7 cm tumor reaching to the carina would have been treated with SBRT only by one center. CONCLUSION: Within DEGRO working group on stereotactic radiotherapy, SBRT for small (<4 cm) early stage NSCLC is a common indication, if the minimal distance to the main bronchi is at least 2 cm. The controversy on the treatment of larger and more central tumors will hopefully be solved by ongoing prospective clinical trials.

Intrafractional dose variation and beam configuration in carbon ion radiotherapy for esophageal cancer.

BACKGROUND: In carbon ion radiotherapy (CIR) for esophageal cancer, organ and target motion is a major challenge for treatment planning due to potential range deviations. This study intends to analyze the impact of intrafractional variations on dosimetric parameters and to identify favourable settings for robust treatment plans. METHODS: We contoured esophageal boost volumes in different organ localizations for four patients and calculated CIR-plans with 13 different beam geometries on a free-breathing CT. Forward calculation of these plans was performed on 4D-CT datasets representing seven different phases of the breathing cycle. Plan quality was assessed for each patient and beam configuration. RESULTS: Target volume coverage was adequate for all settings in the baseline CIR-plans (V95 > 98% for two-beam geometries, > 94% for one-beam geometries), but reduced on 4D-CT plans (V95 range 50-95%). Sparing of the organs at risk (OAR) was adequate, but range deviations during the breathing cycle partly caused critical, maximum doses to spinal cord up to 3.5x higher than expected. There was at least one beam configuration for each patient with appropriate plan quality. CONCLUSIONS: Despite intrafractional motion, CIR for esophageal cancer is possible with robust treatment plans when an individually optimized beam setup is selected depending on tumor size and localization.

Intra-individual comparison of (68)Ga-PSMA-11-PET/CT and multi-parametric MR for imaging of primary prostate cancer.

PURPOSE: Multi-parametric magnetic resonance imaging (MP-MRI) is currently the most comprehensive work up for non-invasive primary tumor staging of prostate cancer (PCa). Prostate-specific membrane antigen (PSMA)-Positron emission tomography-computed tomography (PET/CT) is presented to be a highly promising new technique for N- and M-staging in recurrent PCa-patients. The actual investigation analyses the potential of (68)Ga-PSMA11-PET/CT to assess the extent of primary prostate cancer by intra-individual comparison to MP-MRI. METHODS: In a retrospective study, ten patients with primary PCa underwent MP-MRI and PSMA-PET/CT for initial staging. All tumors were proven histopathological by biopsy. Image analysis was done in a quantitative (SUVmax) and qualitative (blinded read) fashion based on PI-RADS. The PI-RADS schema was then translated into a 3D-matrix and the euclidian distance of this coordinate system was used to quantify the extend of agreement. RESULTS: Both MP-MRI and PSMA-PET/CT presented a good allocation of the PCa, which was also in concordance to the tumor location validated in eight-segment resolution by biopsy. An Isocontour of 50 % SUVmax in PSMA-PET resulted in visually concordant tumor extension in comparison to MP-MRI (T2w and DWI). For 89.4 % of sections containing a tumor according to MP-MRI, the tumor was also identified in total or near-total agreement (euclidian distance ≤1) by PSMA-PET. Vice versa for 96.8 % of the sections identified as tumor bearing by PSMA-PET the tumor was also found in total or near-total agreement by MP-MRI. CONCLUSIONS: PSMA-PET/CT and MP-MRI correlated well with regard to tumor allocation in patients with a high pre-test probability for large tumors. Further research will be needed to evaluate its value in challenging situation such as prostatitis or after repeated negative biopsies.

PSMA PET/CT with Glu-urea-Lys-(Ahx)-[68Ga(HBED-CC)] versus 3D CT volumetric lymph node assessment in recurrent prostate cancer.

PURPOSE: PET/CT with the PSMA ligand is a powerful new method for the early detection of nodal metastases in patients with biochemical relapse. The purpose of this retrospective investigation was to evaluate the volume and dimensions of nodes identified by Glu-urea-Lys-(Ahx)-[(68)Ga(HBED-CC)] ((68)Ga-PSMA-11) in the setting of recurrent prostate cancer. METHODS: All PET/CT images were acquired 60 ± 10 min after intravenous injection of (68)Ga-PSMA-11 (mean dose 176 MBq). In 21 patients with recurrent prostate cancer and rising PSA, 49 PSMA-positive lymph nodes were identified. Using semiautomated lymph node segmentation software, node volume and short-axis and long-axis dimensions were measured and compared with the maximum standardized uptake values (SUVmax). Round nodes greater than or equal to 8 mm were considered positive by morphological criteria alone. The percentage of nodes identified by elevated SUVmax but not by conventional morphological criteria was determined. RESULTS: The mean volume of (68)Ga-PSMA-11-positive nodes was 0.5 ml (range 0.2 - 2.3 ml), and the mean short-axis diameter was 5.8 mm (range 2.4 - 13.3 mm). In 7 patients (33.3 %) with 31 PSMA-positive nodes only 11 (36 %) were morphologically positive based on diameters >8 mm on CT. In the remaining 14 patients (66.7 %), 18 (37 %) of PSMA positive lymph nodes had short-axis diameters <8 mm with a mean short-axis diameter of 5.0 mm (range 2.4 - 7.9 mm). Thus, in this population, (68)Ga-PSMA-11 PET/CT detected nodal recurrence in two-thirds of patients who would have been missed using conventional morphological criteria. CONCLUSION: (68)Ga-PSMA-11 PET/CT is more sensitive than CT based 3D volumetric lymph node evaluation in determining the node status of patients with recurrent prostate cancer, and is a promising method of restaging prostate cancers in this setting.

[Salvage surgery in esophageal cancer : Feasibility in patients after definitive radiochemotherapy (> 50 Gy)]. / Salvage-Chirurgie bei Ösophaguskarzinomen : Sinnvoll bei Patienten nach definitiver Radio(chemo)therapie (> 50 Gy)?

BACKGROUND: Salvage surgery as an additional therapy option is currently discussed for an increasing number of patients with esophageal cancer after definitive radio(chemo)therapy after tumor progression, recurrence or on explicit request of the patient. OBJECTIVES: The objective of this study was an analysis of the surgical option of salvage esophagectomy after definitive radiation in patients with esophageal cancer. Additionally the current literature on this topic was evaluated. MATERIAL AND METHODS: A total of 92 patients with esophageal cancer from a prospective database were included in this study who underwent esophagectomy either after neoadjuvant radio(chemo)therapy (< 50 Gy) or definitive radio(chemo)therapy (> 50 Gy) between 2002 and 2012. The analysis was performed retrospectively. RESULTS: The median survival of the two groups of patients was not significantly different after initial diagnosis with 24.2 months (95 % CI 0.0-51.93) for patients undergoing definitive radio(chemo)therapy and 30.7 months (95 % CI 9.3-52.2) for patients after neoadjuvant therapy (p = 0.96). Both patient groups showed no differences in pretherapeutic characteristics and response to radio(chemo)therapy. Postoperative complications and perioperative mortality were not different. DISCUSSION: Salvage esophagectomy is now an additional treatment option after definitive radio(chemo)therapy in patients with esophageal cancer. In preselected patients with tumor recurrence, progression or with a strong wish for surgical therapy, salvage surgery should be discussed in interdisciplinary tumor boards after exclusion of distant metastases.

[Radiotherapeutic concepts in cancer of unknown primary site]. / Strahlentherapeutische Konzepte beim CUP-Syndrom.

BACKGROUND: The term cancer of unknown primary (CUP) encompasses a group of entities which differ to a great extent regarding etiology, prognosis and therapeutic management. OBJECTIVES: The aim of the study was an elaboration of the role of radiotherapy in CUP syndrome. MATERIAL AND METHODS: Systematic literature search and specification of the available treatment options. RESULTS: Radiotherapy is an integral part of interdisciplinary management approaches for patients with CUP in both curative and palliative situations. Radio-oncological techniques, such as intensity-modulated radiotherapy and stereotactic body radiotherapy increase the therapeutic window. Modern diagnostic modalities from radiology and nuclear medicine are the cornerstone of radiotherapeutic interventions, especially in terms of target volume definition and pretherapeutic staging. In the interdisciplinary setting radiation oncology offers the possibility of curative and often organ preserving approaches in patients with axillary and cervical CUP. In addition, improvement and preservation of quality of life can be achieved in patients with metastatic disease. CONCLUSION: Radiation oncology is a crucial component of the interdisciplinary management of patients with CUP. Therapeutic decisions in patients with CUP should be made in an interdisciplinary setting.

Tomotherapy radiosurgery for arteriovenous malformations--current possibilities and future options with helical tomotherapy dynamic jaws?

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.

Preoperative therapy of esophagogastric cancer: the problem of nonresponding patients.

INTRODUCTION: Preoperative treatment is nowadays standard for locally advanced esophagogastric cancer in Europe. Surprisingly, little attention has been paid to nonresponders so far. The aim of our retrospective exploratory study was the comparison of responder, nonresponder, and primary resected patients in respect of outcome considering the tumor entity. PATIENTS AND METHODS: From 2001-2011, 607 patients with locally advanced esophagogastric carcinoma (adenocarcinoma of the esophagogastric junction (AEG), n = 293; squamous cell cancer (SCC), n = 111; gastric cancer, n = 203) after preoperative treatment (n = 281) or primary resection (n = 326) were included. Histopathological response evaluation (Becker criteria) was available for 263. RESULTS: A total of 76/263 (28.9 %) were responders (<10 % residual tumor). There was an association of response with increased R0 resections (p < 0.001) but also with a higher complication rate (p = 0.008) compared to nonresponse and primary surgery. Mortality was not influenced. Increased R0 resections after response were confirmed in every tumor entity (AEG, p = 0.010; SCC, p = 0.023; gastric cancer, p = 0.006). Median survival was best for responders with 43.5 months [95 % confidence interval (CI), 27.9-59.1], followed by nonresponders with 24.3 months (95 % CI, 21.6-27.0) and primary resected patients with 20.8 months (95 % CI, 17.7-23.9; p = 0.002). AEG (p = 0.012) and gastric cancer (p = 0.017) revealed identical results, but in the subgroup of SCC, the survival of nonresponders (median, 11.6 months; 95 % CI, 6.9-16.3) was even worse than for primary resected patients (median, 23.8 months; 95 % CI, 1.7-46.0; p = 0.012). CONCLUSION: The histopathological response rate was low. Generally, nonresponding patients with AEG or gastric cancer seem not to have a disadvantage compared to primary resected patients, but nonresponders with SCC have a worse prognosis, which strengthens the demand for a critical patient selection in surgery for this tumor entity.

Breast cancer and funnel chest. Comparing helical tomotherapy and three-dimensional conformal radiotherapy with regard to the shape of pectus excavatum.

BACKGROUND AND PURPOSE: Preserving lung, heart, and the contralateral breast from toxicity is a technical challenge in women with funnel chest, who require breast irradiation. The purpose of this study was to determine whether helical tomotherapy (HT) offers an advantage compared to three-dimensional (3D) conformal radiotherapy (CRT) for patients with pectus excavatum with regard to its shape. PATIENTS AND METHODS: Ten breast cancer patients with pectus excavatum were graded into a low or high deformation group using different indices, measured and calculated by using the planning CT. A planning comparison was performed, creating plans for CRT and HT. Target uniformity, target conformity, and exposure to the organs at risk (OARs) were compared. RESULTS: The uniformity and conformity of the target dose distribution and the median/average dose of the planning target volume (PTV) was inferior in CRT compared to HT in both deformation groups. By using tomotherapy, the volume of the lungs, the contralateral breast, and the heart, which received high dose exposure, could be significantly reduced. Tomotherapy plans led to a significantly higher low dose exposure to the lungs and contralateral breast. CONCLUSION: This is the first study which evaluates a group of 10 breast cancer patients with funnel chest. Better uniformity and conformity combined with a significant reduction of high dose exposure to the OARs can be reached using tomotherapy. However, tomotherapy plans have a significantly larger volume of low dose to the lungs and contralateral breast. Therefore, the stochastic risk should be considered after low dose exposure in women with low deformation.

[Radiotherapy for locally advanced prostate cancer]. / Radiotherapie beim lokal fortgeschrittenen Prostatakarzinom.

Technical developments in radiation oncology have led to major improvements in the treatment of locally advanced prostate cancer. This article summarizes the publications on dose escalation, including the side effects. The effect of additional hormonal therapy and irradiation of the pelvic lymphatics is also discussed.

[What is the impact of new radiotherapy techniques?]. / Was leisten die neuen Bestrahlungstechniken?

Radiation oncology, along with surgery and chemotherapy, is one of the cornerstones in the treatment of head and neck tumors. Within the last years, this field has experienced a remarkable evolution of new technical possibilities. New imaging modalities have been introduced into radiation planning and into linear accelerators themselves. In addition, new techniques enable the tailor-made conformation of radiation beams and dose distributions to complex tumor geometries. At the same time, organs at risk can be spared, and long-term toxicities are considerably reduced. This report presents the new techniques in radiation oncology and describes the effects on new treatment options and patients' quality of life.

Treatment of non-small cell lung cancer with intensity-modulated radiation therapy in combination with cetuximab: the NEAR protocol (NCT00115518).

BACKGROUND: Even today, treatment of Stage III NSCLC still poses a serious challenge. So far, surgical resection is the treatment of choice. Patients whose tumour is not resectable or who are unfit to undergo surgery are usually referred to a combined radio-chemotherapy. However, combined radio-chemotherapeutic treatment is also associated with sometimes marked side effects but has been shown to be more efficient than radiation therapy alone. Nevertheless, there is a significant subset of patients whose overall condition does not permit administration of chemotherapy in a combined-modality treatment. It could be demonstrated though, that NSCLCs often exhibit over-expression of EGF-receptors hence providing an excellent target for the monoclonal EGFR-antagonist cetuximab (Erbitux) which has already been shown to be effective in colorectal as well as head-and-neck tumours with comparatively mild side-effects. METHODS/DESIGN: The NEAR trial is a prospective phase II feasibility study combining a monoclonal EGF-receptor antibody with loco-regional irradiation in patients with stage III NSCLC. This trial aims at testing the combination's efficacy and rate of development of distant metastases with an accrual of 30 patients. Patients receive weekly infusions of cetuximab (Erbitux) plus loco-regional radiation therapy as intensity-modulated radiation therapy. After conclusion of radiation treatment patients continue to receive weekly cetuximab for 13 more cycles. DISCUSSION: The primary objective of the NEAR trial is to evaluate toxicities and feasibility of the combined treatment with cetuximab (Erbitux) and IMRT loco-regional irradiation. Secondary objectives are remission rates, 3-year-survival and local/systemic progression-free survival.

Influence of intra-fractional breathing movement in step-and-shoot IMRT.

Efforts have been made to extend the application of intensity-modulated radiotherapy to a variety of organs. One of the unanswered questions is whether breathing-induced organ motion may lead to a relevant over- or underdosage, e.g., in treatment plans for the irradiation of lung cancer. Theoretical considerations have been made concerning the different kinds of IMRT but there is still a lack of experimental data. We examined 18 points in a fraction of a clinical treatment plan of a NSCLC delivered in static IMRT with a new phantom and nine ionization chambers. Measurements were performed at a speed of 12 and 16 breathing cycles per minute. The dose differences between static points and moving target points ranged between -2.4% and +5.5% (mean: +0.2%, median: -0.1%) when moving with 12 cycles min(-1) and between -3.6% and +5.0% (mean: -0.4%, median: -0.6%) when moving with 16 cycles min(-1). All differences of measurements with and without movements were below 5%, with one exception. In conclusion, our results underline that at least in static IMRT breathing effects (concerning target dose coverage) due to interplay effects between collimator leaf movement and target movement are of secondary importance and will not reduce the clinical value of IMRT in the step-and-shoot technique for irradiation of thoracic targets.