[Show abstract][Hide abstract] ABSTRACT: Background:
The aim of the thesis is to improve radiation plans of patients with locally advanced, unresectable pancreatic cancer by using carbon ion and proton beams.
Patients and methods:
Using the treatment planning system Syngo RT Planning (Siemens, Erlangen, Germany) a total of 50 treatment plans have been created for five patients with the dose schedule 15 × 3 Gy(RBE). With reference to the anatomy, five field configurations were considered to be relevant. The plans were analyzed with respect to dose distribution and individual anatomy, and compared using a customized index.
Within the index the three-field configurations yielded the best results, though with a high variety of score points (field setup 5, carbon ion: median 74 (range 48-101)). The maximum dose in the myelon is low (e.g. case 3, carbon ion: 21.5 Gy(RBE)). A single posterior field generally spares the organs at risk, but the maximum dose in the myelon is high (e.g. case 3, carbon ion: 32.9 Gy(RBE)). Two oblique posterior fields resulted in acceptable maximum doses in the myelon (e.g. case 3, carbon ion: 26.9 Gy(RBE)). The single-field configuration and the two oblique posterior fields had a small score dispersion (carbon ion: median 66 and 58 (range 62-72 and 40-69)). In cases with topographic proximity of the organs at risk to the target volume, the single-field configuration scored as well as the three-field configurations.
In summary, the three-field configurations showed the best dose distributions. A single posterior field seems to be robust and beneficial in case of difficult topographical conditions and topographical proximity of organs at risk to the target volume. A setup with two oblique posterior fields is a reasonable compromise between three-field and single-field configurations.
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Recently, information availability has become more elaborate and widespread, and treatment decisions are based on a multitude of factors. Gathering relevant data, also referred to as Big Data, is therefore critical for reaching the best patient care, and enhancing interdisciplinary and clinical research. Combining patient data from all involved systems is essential to prepare unstructured data for analyses. This demands special coordination in data management. Our study aims to characterize current developments in German-speaking hospital departments and practices. We successfully conducted the survey with the members of the Deutsche Gesellschaft für Radioonkologie (DEGRO).
A questionnaire was developed consisting of 17 questions related to data management, documentation and clinical trial analyses, reflecting the clinical topics such as basic patient information, imaging, follow-up information as well as connection of documentation tools with radiooncological treatment planning machines.
A total of 44 institutions completed the online survey (University hospitals n = 17, hospitals n = 13, practices/institutes n = 14). University hospitals, community hospitals and private practices are equally equipped concerning IT infrastructure for clinical use. However, private practices have a low interest in research work. All respondents stated the biggest obstacles about introducing a documentation system into their unit lie in funding and support of the central IT departments. Only 27 % (12/44) of responsible persons are specialists for documentation and data management.
Our study gives an understanding of the challenges and solutions we need to be looking at for medical data storage. In the future, inter-departmental cross-links will enable the radiation oncology community to generate large-scale analyses.
[Show abstract][Hide abstract] ABSTRACT: Heat-shock protein 70 (Hsp70) is frequently found on the plasma membrane of a large number of malignant tumors including non-small cell lung cancer (NSCLC) and gets released into the blood circulation in lipid vesicles. On the one hand, a membrane (m)Hsp70-positive phenotype correlates with a high aggressiveness of the tumor; on the other hand, mHsp70 serves as a target for natural killer (NK) cells that had been pre-stimulated with Hsp70-peptide TKD plus low-dose interleukin-2 (TKD/IL-2). Following activation, NK cells show an up-regulated expression of activatory C-type lectin receptors, such as CD94/NKG2C, NKG2D, and natural cytotoxicity receptors (NCRs; NKp44, NKp46, and NKp30) and thereby gain the capacity to kill mHsp70-positive tumor cells. With respect to these results, the efficacy of ex vivo TKD/IL-2 stimulated, autologous NK cells is currently tested in a proof-of-concept phase II clinical trial in patients with squamous cell NSCLC after radiochemotherapy (RCT) at the TUM. Inclusion criteria are histological proven, non-resectable NSCLC in stage IIIA/IIIB, clinical responses to RCT and a mHsp70-positive tumor phenotype. The mHsp70 status is determined in the serum of patients using the lipHsp70 ELISA test, which enables the quantification of liposomal and free Hsp70. Squamous cell and adeno NSCLC patients had significantly higher serum Hsp70 levels than healthy controls. A significant correlation of serum Hsp70 levels with the gross tumor volume was shown for adeno and squamous cell NSCLC. However, significantly elevated ratios of activated CD69(+)/CD94(+) NK cells that are associated with low serum Hsp70 levels were observed only in patients with squamous cell lung cancer. These data might provide a first hint that squamous cell NSCLC is more immunogenic than adeno NSCLC.
Frontiers in Immunology 11/2015; 6. DOI:10.3389/fimmu.2015.00556
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to assess the effect of breathing motion on the delivered dose in esophageal cancer 3-dimensional (3D)-conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), and volumetric modulated arc therapy (VMAT). We assessed 16 patients with esophageal cancer. All patients underwent 4D-computed tomography (4D-CT) for treatment planning. For each of the analyzed patients, 1 3D-CRT, 1 IMRT, and 1 VMAT (RapidArc-RA) plan were calculated. Each of the 3 initial plans was recalculated on the 4D-CT (for the maximum free inspiration and maximum free expiration) to assess the effect of breathing motion. We assessed the minimum dose (Dmin) and mean dose (Dmean) to the esophagus within the planning target volume, the volume changes of the lungs, the Dmean and the total lung volume receiving at least 40Gy (V40), and the V30, V20, V10, and V5. For the heart we assessed the Dmean and the V25. Over all techniques and all patients the change in Dmean as compared with the planned Dmean (planning CT [PCT]) to the esophagus was 0.48% in maximum free inspiration (CT_insp) and 0.55% in maximum free expiration (CT_exp). The Dmin CT_insp change was 0.86% and CT_exp change was 0.89%. The Dmean change of the lungs (heart) was in CT_insp 1.95% (2.89%) and 3.88% (2.38%) in CT_exp. In all, 4 patients had a clinically relevant change of the dose (≥ 5% Dmean to the heart and the lungs) between inspiration and expiration. These patients had a very cranially or caudally situated tumor. There are no relevant differences in the delivered dose to the regions of interest among the 3 techniques. Breathing motion management could be considered to achieve a better sparing of the lungs or heart in patients with cranially or caudally situated tumors.
Medical dosimetry: official journal of the American Association of Medical Dosimetrists 09/2015; DOI:10.1016/j.meddos.2015.07.002 · 0.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
To retrospectively access outcome and prognostic parameters of linear accelerator-based stereotactic radiosurgery in brain metastases from malignant melanoma.
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.
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 < 0.001), the response to stereotactic radiosurgery (log-rank, p < 0.001), the number of brain metastases (log-rank, p = 0.007), the recursive partitioning analysis class (log-rank, p = 0.027) and the diagnosis-specific graded prognostic assessment score (log-rank, p = 0.011) were prognostic for overall survival. The most common clinical side effect was headache common toxicity criteria grade I. The most common radiological finding during follow-up was localized edema within the stereotactic radiosurgery high dose region.
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.
BMC Cancer 07/2015; 15(1):537. DOI:10.1186/s12885-015-1517-1 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Novel techniques in radiation oncology have significantly improved the therapeutic window in locally advanced pancreatic cancer LAPC. In about one third of the patients, chemoradiation can lead to secondary resectability, contributing to an increase in outcome. Dose-escalation approaches using stereotactic body radiotherapy (SBRT) or advanced treatments such as intensity-modulated radiotherapy (IMRT) can exploit the biological benefits of hypofractionation, or use "dose painting" approaches to target defined subvolumes. Prognostic subgroups of patients have been identified, based on molecular markers such as CA 19-9, nutritional factors, diabetes or immunological properties of tumor and normal tissue.
The aim of the present manuscript is to summarize data on downsizing for locally advanced pancreatic cancer (LAPC) and to elucidate the role of individualized radiotherapy (iRT).
Future concepts focus on iRT based on prognostic factors leading to a true personalized treatment.
Langenbeck s Archives of Surgery 07/2015; 400(7). DOI:10.1007/s00423-015-1309-8 · 2.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The benefits of new innovations in glioblastoma therapies should not be curtailed as a result of delays in commencement of radiation therapy, caused by clinical circumstances as well as diagnostic procedures. This study evaluates whether delays in chemo-radiotherapy after surgery, while determining O6-methylguanine-DNA-methyltransferase (MGMT) promoter status, affect the survival rates of patients with glioblastoma (GBM).
Our sample comprised 50 GBM patients in a retrospective analysis of three prospective studies that focused on combined radiotherapy and required MGMT promoter-status testing as inclusion criteria. Results were compared with a reference group of 127 favourable GBM cases (Karnofsky performance-status scale ≥ 70), in which the patients underwent standard postoperative chemo-radiotherapy with temozolomide. Survival time was calculated using the Kaplan-Meier method, and a multivariate analysis of the delays between surgical and radiotherapy procedures was performed using the Cox regression model.
The study group's median overall survival time was 16.2 months (with a range of 2 to 56 months), versus the reference group's survival time of 18.2 months (with a range of 1 to 92 months) (p = 0.64). The delay between surgery and radiotherapy was increased by 8 days in the study patients (p < 0.001), with a median delay of 35 days (range: 18-49 days) corresponding to the typical 27-day delay (range: 5-98 days) for those in the reference group. Univariate and multivariate analyses did not show any negative association between survival time and delaying radiation therapy to determine MGMT-promoter status; commencement of radiation therapy sooner than 24 days after surgery was the threshold for significantly decreased overall survival (p = 0.01) and progression-free (p = 0.03) survival.
Delaying postoperative chemoradiation for GBM patients-carried out in order to determine MGMT-promoter status-did not have a negative impact on survival time. Indeed, the data of the present study shows that initiating radiation therapy sooner than 24 days after surgery has a negative impact on progression and survival.
BMC Cancer 07/2015; 15(1):558. DOI:10.1186/s12885-015-1545-x · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: With the development of more conformal and precise radiation techniques such as Intensity-Modulated Radiotherapy (IMRT), Stereotactic Body Radiotherapy (SBRT) and Image-Guided Radiotherapy (IGRT), patients with hepatic tumors could be treated with high local doses by sparing normal liver tissue. However, frequently occurring large HCC tumors are still a dosimetric challenge in spite of modern high sophisticated RT modalities. This interventional clinical study has been set up to evaluate the value of different fiducial markers, and to use the modern imaging methods for further treatment optimization using physical and informatics approaches.
Surgically implanted radioopaque or electromagnetic markers are used to detect tumor local-ization during radiotherapy. The required markers for targeting and observation during RT can be implanted in a previously defined optimal position during the oncologically indicated operation. If there is no indication for a surgical resection or open biopsy, markers may be inserted into the liver or tumor tissue by using ultrasound-guidance. Primary study aim is the detection of the patients´ anatomy at the time of RT by observation of the marker position during the indicated irradiation (IGRT). Secondary study aims comprise detection and recording of 3D liver and tumor motion during RT. Furthermore, the study will help to develop technical strategies and mechanisms based on the recorded information on organ motion to avoid inaccurate dose application resulting from fast organ motion and deformation.
This is an open monocentric non-randomized, prospective study for the evaluation of organ motion using interstitial markers or implantable radiotransmitter. The trial will evaluate the full potential of different fiducial markers to further optimize treatment of moving targets, with a special focus on liver lesions.
[Show abstract][Hide abstract] ABSTRACT: The aim of the study was to assess the importance of surrounding tissues for the delineation of moving targets in tissue-specific phantoms and to find optimal settings for lung, soft tissue, and liver tumors.
Tumor movement was simulated by a water-filled table tennis ball (target volume, TV). Three phantoms were created: corkboards to simulate lung tissue (lung phantom, LunPh), animal fat as fatty soft tissue (fatty tissue phantom, FatPh), and water enhanced with contrast medium as the liver tissue (liver phantom, LivPh). Slow planning three-dimensional compute tomography images (3D-CTs) were acquired with and without phantom movements. One-dimensional tumor movement (1D), three-dimensional tumor movement (3D), as well as a real patient's tumor trajectories were simulated. The TV was contoured using two lung window settings, two soft-tissue window settings, and one liver window setting. The volumes were compared to mathematical calculated values.
TVs were underestimated in all phantoms due to movement. The use of soft-tissue windows in the LivPh led to a significantunderestimation of the TV (70.8 % of calculated TV). When common window settings [LunPh + 200 HU/-1,000 HU (upper window/lower window threshold); FatPh: + 240 HU/-120 HU; LivPh: + 175 HU/+ 50 HU] were used, the contoured TVs were: LivPh, 84.0 %; LunPh, 93.2 %, and FatPh, 92.8 %. The lower window threshold had a significant impact on the size of the delineated TV, whereas changes of the upper threshold led only to small differences.
The decisive factor for window settings is the lower window threshold (for adequate TV delineation in the lung and fatty-soft tissue it should be lower than density values of surrounding tissue). The use of a liver window should be considered.
Strahlentherapie und Onkologie 06/2015; 191(9). DOI:10.1007/s00066-015-0862-y · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The primary objective was to assess the different reasons for refusal of surgical resection (SR) in patients with esophageal squamous cell cancer (ESCC), who were initially planned for neoadjuvant radiochemotherapy (N-RCT) + SR, but SR was not performed after N-RCT.
From 1988 to 2011, 311 patients with ESCC were treated with N-RCT in a tertiary referral center for esophageal diseases. Fifty-three patients were analyzed who received RCT with 40-45 Gy and concomitant chemotherapy in neoadjuvant intention, but in whom the treatment was stopped or switched to definitive RCT due to progression, patient decision, or new findings.
The reasons for refusal of SR for these 53 patients were as follows: (1) patients' or physicians' preference for the planned treatment was changed during the N-RCT, such that RCT was continued to a curative dose without a break (group 1, n = 23, 44%); (2) patients were restaged after 4 weeks, and the tumor board decided to continue RCT because R0 resection was unlikely and/or patients were medically unfit (group 2, n = 15, 28%); (3) patients refused continuation of any treatment (group 3, n = 15, 28%). Refusal of SR was significantly more likely in patients with longitudinal tumor dimension >8 cm and those with an Eastern Cooperative Oncology Group performance status score of 2. Median follow-up time from the start of N-RCT was 57 months (range 1-137 months). The survival rates at 2 and 5 years were 36 ± 7% and 27 ± 7%, respectively. Group 1 had significantly longer survival.
The planned N-RCT+SR could not be completed in a considerable number of patients in a tertiary referral center. More strict selection criteria for multimodality treatment including SR could spare some of these patients an incomplete treatment and probably lead to increased utilization of definitive RCT.
[Show abstract][Hide abstract] ABSTRACT: The purpose of the study was to evaluate the effect of radiation therapy and chemoradiation with gemcitabine (GEM) after R1 resection in patients with pancreatic adenocarcinoma (PAC).
We performed a retrospective analysis of 25 patients who were treated with postoperative radiotherapy (RT) or chemoradiation (CRT) after surgery with microscopically positive resection margins for primary pancreatic cancer (PAC). Median age was 60 years (range 34 to 74 years), and there were 17 male and 8 female patients. Fractionated RT was applied with a median dose of 49.6 Gy (range 36 to 54 Gy). Eight patients received additional intraoperative radiotherapy (IORT) with a median dose of 12 Gy.
Median overall survival (mOS) of all treated patients was 22 months (95% confidence interval (CI) 7.9 to 36.1 months) after date of resection and 21.1 months (95% CI 7.6 to 34.6 months) after start of (C)RT. Median progression-free survival (mPFS) was 13.0 months (95% CI 0.93 to 25 months). Grading (G2 vs. G3, P = 0.005) and gender (female vs. male, P = 0.01) were significantly correlated with OS. There was a significant difference in mPFS between male and female patients (P = 0.008). A total of 11 from 25 patients experienced local tumour progression, and 19 patients were diagnosed with either locoregional or distant failure.
We demonstrated that GEM-based CRT can be applied in analogy to neoadjuvant protocols in the adjuvant setting for PAC patients at high risk for disease recurrence after incomplete resection. Patients undergoing additive CRT have a rather good OS and PFS compared to historical control patient groups.
World Journal of Surgical Oncology 04/2015; 13(1):149. DOI:10.1186/s12957-015-0560-3 · 1.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Heat shock protein 70 (Hsp70) is frequently overexpressed in tumor cells. An unusual cell surface localization could be demonstrated on a large variety of solid tumors including lung, colorectal, breast, squamous cell carcinomas of the head and neck, prostate and pancreatic carcinomas, glioblastomas, sarcomas and hematological malignancies, but not on corresponding normal tissues. A membrane (m)Hsp70-positive phenotype can be determined either directly on single cell suspensions of tumor biopsies by flow cytometry using cmHsp70.1 monoclonal antibody or indirectly in the serum of patients using a novel lipHsp70 ELISA. A mHsp70-positive tumor phenotype has been associated with highly aggressive tumors, causing invasion and metastases and resistance to cell death. However, natural killer (NK), but not T cells were found to kill mHsp70-positive tumor cells after activation with a naturally occurring Hsp70 peptide (TKD) plus low dose IL-2 (TKD/IL-2). Safety and tolerability of ex vivo TKD/IL-2 stimulated, autologous NK cells has been demonstrated in patients with metastasized colorectal and NSCLC in a phase I clinical trial. Based on promising clinical results of the previous study, a phase II randomized clinical study was initiated in 2015. The primary objective of this multicenter proof-of-concept trial is to examine whether an adjuvant treatment of NSCLC patients after platinum based radiochemotherapy with TKD/IL-2 activated, autologous NK cells is clinically effective. As a mHsp70-positive tumor phenotype is associated with poor clinical outcome only mHsp70-positive tumor patients will be recruited into the trial. The primary endpoint of this study will be the comparison of the progression-free survival of patients treated with ex vivo activated NK cells compared to patients who were treated with radiochemotherapy alone. As secondary endpoints overall survival, toxicity, quality-of-life and biological responses will be determined in both study groups.
Frontiers in Immunology 04/2015; 6:162. DOI:10.3389/fimmu.2015.00162