Stephanie E Combs

Universität Heidelberg, Heidelburg, Baden-Württemberg, Germany

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Publications (167)529.33 Total impact

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    ABSTRACT: (68)Ga-DOTATOC-PET/CT is a well-established method for detecting and targeting the volume definition of meningiomas prior to radiotherapy. Moreover, there is evidence that this method is able to detect meningiomas with higher sensitivity than the goldstandard MRI. Since the hybrid PET/MRI scanner became available in the past few years, the next stage of development could consequently evolve by evaluating the feasibility of a hybrid PET/MRI scanner using (68)Ga-DOTATOC for detecting meningiomas.
    Neuro-oncology. 07/2014;
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    ABSTRACT: Human glioblastomas may be hierarchically organized. Within this hierarchy, glioblastoma-initiating cells (GIC) have been proposed to be more resistant to radiochemotherapy and responsible for recurrence. Here, established stem cell markers and stem cell attributed characteristics such as self-renewal capacity and tumorigenicity have been profiled in primary glioblastoma cultures to predict radiosensitivity. Furthermore, the sensitivity to radiotherapy of different subpopulations within a single primary glioblastoma culture was analyzed by a flow cytometric approach using Nestin, SRY (sex determining region Y)-box 2 (SOX2) and glial fibrillary acidic protein (GFAP). The protein expression of Nestin and SOX2 as well as the mRNA levels of Musashi1, L1CAM, CD133, Nestin and PLAGL2 inversely correlated with radioresistance in regard to the clonogenic potential. Only CD44 protein expression correlated positively with radioresistance. In terms of proliferation, Nestin protein expression and Musashi1, PLAGL2 and CD133 mRNA levels inversely correlated with radioresistance. Higher expression of stem cell markers does not correlate with resistance to radiochemotherapy in a TCGA (the cancer genome atlas) glioblastoma collective. SOX2 expressing subpopulations exist within single primary glioblastoma cultures. These subpopulations predominantly form the proliferative pool of the primary cultures and are sensitive to irradiation. Thus, profiling of established stem cell markers revealed a surprising result. Except CD44, the tested stem cell markers showed an inverse correlation between expression and radioresistance. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 06/2014; · 3.97 Impact Factor
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    ABSTRACT: To asses the impact of CA 19-9 and weight loss/gain on outcome after neoadjuvant chemoradiation (CRT) in patients with locally advanced pancreatic cancer (LAPC).
    Annals of Surgical Oncology 06/2014; · 4.12 Impact Factor
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    ABSTRACT: Purpose: Re-irradiation has been shown to be a valid option with proven efficacy for recurrent high-grade glioma patients. Overall, up to now it is unclear which patients might be optimal candidates for a second course of irradiation. A recently reported prognostic score developed by Combs et al. may guide treatment decisions and thus, our mono-institutional cohort served as validation set to test its relevance for clinical practice.Patients and methods: The prognostic score is built upon histology, age (< 50 vs. >= 50 years) and the time between initial radiotherapy and re-irradiation (<= 12 vs. > 12 months). This score was initially introduced to distinguish patients with excellent (0 points), good (1 point), moderate (2 points) and poor (3-4 points) post-recurrence survival (PRS) after re-irradiation. Median prescribed radiation dose during re-treatment of recurrent malignant glioma was 36Gy in 2 Gy single fractions. A substantial part of the patients was additionally treated with bevacizumab (10 mg/kg intravenously at d1 and d15 during re-irradiation).
    Radiation oncology (London, England). 06/2014; 9(1):128.
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    ABSTRACT: Pancreatic cancer (PAC) patients experience a high rate of locoregional recurrences and distant metastasis finally leading to their demise even after curatively-intended multidisciplinary treatment approaches including surgery, chemotherapy and radiotherapy. However, clinical reports on bone and brain metastases in PAC patients are extremely rare and thus timing and dose description are not well defined. Our work therefore summarizes a mono-institutional experience on the use of radiotherapy (RT) for PAC patients with metastatic disease with the aim of identifying overall survival and treatment response in this rarely reported patient group.
    European journal of medical research 05/2014; 19(1):24. · 1.10 Impact Factor
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    ABSTRACT: Long-term survival is rare in patients with glioblastoma (GBM). We set out to determine prognostic factors for patients with favorable and poor prognosis in regard of tumor localization to the subventricular zone (SZV). We reviewed the clinical records, pre-operative and post-operative MRI imaging of 50 LTS long-term survivors (LTS) (>3 years) and 50 short-term survivors (STS) (<1 year) with glioblastoma. These groups were matched for clinical characteristics being consistently associated with prolonged or shortened survival. All patients had undergone initial surgery or biopsy to confirm GBM diagnosis followed by radio- or chemoradiotherapy. LTS had a median progression-free survival PFS of 25,4 months (2,3 - 97,8 months) and overall-survival (OS) of 55,9 months (38,2 - 98,6 months) compared to STS who had a significantly lower PFS of 4,2 months (1,4 - 10,2 months) and OS of 6,6 months (2,2 - 11,6 months) (each p < 0,001).Survival analysis showed that age under 60 years (p < 0,001), total resection status (p < 0,001) and tumor localization without SVZ contact (p = 0,05) were significant factors for prolonged survival. Our findings underline that survival in GBM patients is heterogeneous and influenced by multiple factors. This study confirms that tumor location with regard to the SVZ is significantly associated with survival.
    Radiation Oncology 04/2014; 9(1):95. · 2.11 Impact Factor
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    ABSTRACT: Persistent human papilloma virus 16 (HPV16) infections are a major cause of cervical cancer. The integration of the viral DNA into the host genome causes E2 gene disruption which prevents apoptosis and increases host cell motility. In cervical cancer patients, survival is limited by local infiltration and systemic dissemination. Surgical control rates are poor in cases of parametrial infiltration. In these patients, radiotherapy (RT) is administered to enhance local control. However, photon irradiation itself has been reported to increase cell motility. In cases of E2-disrupted cervical cancers, this phenomon would impose an additional risk of enhanced tumor cell motility. Here, we analyze mechanisms underlying photon-increased migration in keratinocytes with differential E2 gene status. Isogenic W12 (intact E2 gene status) and S12 (disrupted E2 gene status) keratinocytes were analyzed in fibronectin-based and serum-stimulated migration experiments following single photon doses of 0, 2, and 10 Gy. Quantitative FACS analyses of integrin expression were performed. Migration and adhesion are increased in E2 gene-disrupted keratinocytes. E2 gene disruption promotes attractability by serum components, therefore, effectuating the risk of local infiltration and systemic dissemination. In S12 cells, migration is further increased by photon RT which leads to enhanced expression of fibronectin receptor integrins. HPV16-associated E2 gene disruption is a main predictor of treatment-refractory cancer virulence. E2 gene disruption promotes cell motility. Following photon RT, E2-disrupted tumors bear the risk of integrin-related infiltration and dissemination.
    Strahlentherapie und Onkologie 03/2014; · 4.16 Impact Factor
  • Strahlentherapie und Onkologie 03/2014; 190(3):319-20. · 4.16 Impact Factor
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    ABSTRACT: Aims and background. To evaluate the long-term outcome of patients with vestibular schwannoma (VS) and neurofibromatosis type 2 (NF2) treated with fractionated stereotactic radiotherapy (FSRT) or stereotactic radiosurgery (SRS).Patients and methods. Sixteen VS in 14 patients with NF2 were treated with FSRT (n = 14) and SRS (n = 2). Patients with tumor progression and/or progression of clinical symptoms were selected for treatment. For patients treated with FSRT a median total dose of 57.6 Gy was prescribed with a median fractionation of 5 × 1.8 Gy per week. For patients who underwent SRS a median single dose of 17 Gy was prescribed to the 80% isodose.Results. FSRT and SRS were well tolerated. Local control rate was 94% for a median follow-up time of 131 months; 2- and 5-year progression-free survival were 100%. The probability of maintaining the pretreatment hearing level was 44%. Useful hearing preservation was 33%. Cranial nerve toxicity was moderate. Trigeminal nerve function worsened in 2 patients (12%) and facial nerve function in 3 patients (19%). One patient developed a new tinnitus. Conclusion. FSRT and SRS are both safe and effective noninvasive and minimally invasive treatment options for patients with VS in the setting of NF2. The long-term local control rates are excellent. Functional hearing preservation is worse in patients with VS and NF2 than in patients with sporadic VS.
    Tumori. 03/2014; 100(2):189-94.
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    ABSTRACT: Studies on the monoclonal VEGF-A antibody bevacizumab gave raise to questions regarding the lack of an overall survival benefit, the optimal timing in the disease course and potential combination and salvage therapies. We retrospectively assessed survival, radiological progression type on bevacizumab and efficacy of salvage therapies in 42 patients with recurrent malignant gliomas who received bevacizumab and nitrosourea sequentially. 15 patients received bevacizumab followed by nitrosourea at progression and 27 patients vice versa. Time to treatment failure, defined as time from initiation of one to failure of the other treatment, was similar in both groups (9.6 vs. 9.2 months, log rank p = 0.19). Progression-free survival on nitrosoureas was comparable in both groups, while progression-free survival on bevacizumab was longer in the group receiving bevacizumab first (5.3 vs. 4.1 months, log rank p = 0.03). Survival times were similar for patients with grade III (n = 9) and grade IV (n = 33) tumors. Progression-free survival on bevacizumab for patients developing contrast-enhancing T1 progression was longer than for patients who displayed a non-enhancing T2 progression. However, post-progression survival times after bevacizumab failure were not different. Earlier treatment with bevacizumab was not associated with better outcome in this series. The fact that earlier as compared to later bevacizumab treatment does not result in a different time to treatment failure highlights the challenge for first-line or recurrence trials with bevacizumab to demonstrate an overall survival benefit if crossover of bevacizumab-naïve patients after progression occurs.
    Journal of Neuro-Oncology 01/2014; · 3.12 Impact Factor
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    ABSTRACT: Time is an important factor during immobilization for radiotherapy (RT) of painful spinal bone metastases. The different RT techniques currently in use have differing impacts on medical staff requirements, treatment planning and radiation delivery. This prospective analysis aimed to evaluate time management during RT of patients with spine metastases, focusing particularly on the impact of image-guided RT (IGRT). Between 21 March 2013 and 17 June 2013, we prospectively documented the time associated with the core work procedures involving the patient during the first day of RT at three different linear accelerators (LINACs). The study included 30 patients; 10 in each of three groups. Groups 1 and 2 were treated with a single photon field in the posterior-anterior direction; group 3 received a three-dimensional conformal treatment plan. The median overall durations of one treatment session were 24 and 25.5 min for the conventional RT groups and 15 min for IGRT group. The longest single procedure was patient immobilization in group 1 (median 9.5 min), whereas this was image registration and matching in groups 2 and 3 (median duration 9.5 and 5 min, respectively). Duration of irradiation (beam-on time) was similar for all groups at 4 or 5 min. The shortest immobilization procedure was observed in group 3 with a median of 3 min, compared to 4 min in group 2 and 9.5 min in group 1. With this analysis, we have shown for the first time that addition of modern IGRT does not extend the overall treatment time for patients with painful bone metastases and can be applied as part of clinical routine in a palliative setting. The choice of treatment technique should be based upon the patient's performance status, as well as the size of the target volume and location of the metastasis.
    Strahlentherapie und Onkologie 01/2014; · 4.16 Impact Factor
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    ABSTRACT: 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. 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. 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. 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.
    Radiation Oncology 01/2014; 9(1):4. · 2.11 Impact Factor
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    ABSTRACT: Purpose Estimation of the actual delivered 4-dimensional (4D) dose in treatments of patients with mobile hepatocellular cancer with scanned carbon ion beam therapy. Methods and Materials Six patients were treated with 4 fractions to a total relative biological effectiveness (RBE)–weighted dose of 40 Gy (RBE) using a single field. Respiratory motion was addressed by dedicated margins and abdominal compression (5 patients) or gating (1 patient). 4D treatment dose reconstructions based on the treatment records and the measured motion monitoring data were performed for the single-fraction dose and a total of 17 fractions. To assess the impact of uncertainties in the temporal correlation between motion trajectory and beam delivery sequence, 3 dose distributions for varying temporal correlation were calculated per fraction. For 3 patients, the total treatment dose was formed from the fractional distributions using all possible combinations. Clinical target volume (CTV) coverage was analyzed using the volumes receiving at least 95% (V95) and 107% (V107) of the planned doses. Results 4D dose reconstruction based on daily measured data is possible in a clinical setting. V95 and V107 values for the single fractions ranged between 72% and 100%, and 0% and 32%, respectively. The estimated total treatment dose to the CTV exhibited improved and more robust dose coverage (mean V95 > 87%, SD < 3%) and overdose (mean V107 < 4%, SD < 3%) with respect to the single-fraction dose for all analyzed patients. Conclusions A considerable impact of interplay effects on the single-fraction CTV dose was found for most of the analyzed patients. However, due to the fractionated treatment, dose heterogeneities were substantially reduced for the total treatment dose. 4D treatment dose reconstruction for scanned ion beam therapy is technically feasible and may evolve into a valuable tool for dose assessment.
    International journal of radiation oncology, biology, physics 01/2014; 89(1):175–181. · 4.59 Impact Factor
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    ABSTRACT: In radiation oncology, where treatment concepts are elaborated in interdisciplinary collaborations, handling distributed, large heterogeneous amounts of data efficiently is very important, yet challenging, for an optimal treatment of the patient as well as for research itself. This becomes a strong focus, as we step into the era of modern personalized medicine, relying on various quantitative data information, thus involving the active contribution of multiple medical specialties. Hence, combining patient data from all involved information systems is inevitable for analyses. Therefore, we introduced a documentation and data management system integrated in the clinical environment for electronic data capture. We discuss our concept and five-year experience of a precise electronic documentation system, with special focus on the challenges we encountered. We specify how such a system can be designed and implemented to plan, tailor and conduct (multicenter) clinical trials, ultimately reaching the best clinical performance, and enhancing interdisciplinary and clinical research.
    Computer methods and programs in biomedicine 01/2014; · 1.56 Impact Factor
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    ABSTRACT: Background Both (18)F-fluorodihydroxyphenylalanine ((18)F-DOPA) and (18)F-fluoroethyltyrosine ((18)F-FET) have already been used successfully for imaging of brain tumors. The aim of this study was to evaluate differences between these 2 promising tracers to determine the consequences for imaging protocols and the interpretation of findings.Methods Forty minutes of dynamic PET imaging were performed on 2 consecutive days with both (18)F-DOPA and (18)F-FET in patients with recurrent low-grade astrocytoma (n = 8) or high-grade glioblastoma (n = 8). Time-activity-curves (TACs), standardized uptake values (SUVs) and compartment modeling of both tracers were analyzed, respectively.ResultsThe TAC of DOPA-PET peaked at 8 minutes p.i. with SUV 5.23 in high-grade gliomas and 10 minutes p.i. with SUV 4.92 in low-grade gliomas. FET-PET peaked at 9 minutes p.i. with SUV 3.17 in high-grade gliomas and 40 minutes p.i. with SUV 3.24 in low-grade gliomas. Neglecting the specific uptake of DOPA into the striatum, the tumor-to-brain and tumor-to-blood ratios were higher for DOPA-PET. Kinetic modeling demonstrated a high flow constant k1 (mL/ccm/min), representing cellular internalization through AS-transporters, for DOPA in both high-grade (k1 = 0.59) and low-grade (k1 = 0.55) tumors, while lower absolute values and a relevant dependency from tumor-grading (high-grade k1 = 0.43; low-grade k1 = 0.33) were observed with FET.ConclusionsDOPA-PET demonstrates superior contrast ratios for lesions outside the striatum, but SUVs do not correlate with grading. FET-PET can provide additional information on tumor grading and benefits from lower striatal uptake but presents lower contrast ratios and requires prolonged imaging if histology is not available in advance due to a more variable time-to-peak.
    Neuro-Oncology 12/2013; · 6.18 Impact Factor
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    ABSTRACT: Characterization of combination effects of chemotherapy drugs with carbon ions in comparison to photons in vitro. The human colon adenocarcinoma cell line WiDr was tested for combinations with camptothecin, cisplatin, gemcitabine and paclitaxel. In addition three other human tumour cell lines (A549: lung, LN-229: glioblastoma, PANC-1: pancreas) were tested for the combination with camptothecin. Cells were irradiated with photon doses of 2, 4, 6 and 8 Gy or carbon ion doses of 0.5, 1, 2 and 3 Gy. Cell survival was assessed using the clonogenic growth assay. Treatment dependent changes in cell cycle distribution (up to 12 hours post-treatment) were measured by FACS analysis after propidium-iodide staining. Apoptosis was monitored for up to 36 hours post-treatment by Nicoletti-assay (with qualitative verification using DAPI staining). All cell lines exhibited the well-known increase of killing efficacy per unit dose of carbon ion exposure, with relative biological efficiencies at 10% survival (RBE10) ranging from 2.3 to 3.7 for the different cell lines. In combination with chemotherapy additive toxicity was the prevailing effect. Only in combination with gemcitabine or cisplatin (WiDr) or camptothecin (all cell lines) the photon sensitivity was slightly enhanced, whereas purely independent toxicities were found with the carbon ion irradiation, in all cases. Radiation-induced cell cycle changes displayed the generally observed dose-dependent G2-arrest with little effect on S-phase fraction for all cell lines for photons and for carbon ions. Only paclitaxel showed a significant induction of apoptosis in WiDr cell line but independent of the used radiation quality. Combined effects of different chemotherapeutics with photons or with carbon ions do neither display qualitative nor substantial quantitative differences. Small radiosensitizing effects, when observed with photons are decreased with carbon ions. The data support the idea that a radiochemotherapy with common drugs and carbon ion irradiation might be as feasible as respective photon-based protocols. The present data serve as an important radiobiological basis for further combination experiments, as well as clinical studies on combination treatments.
    Radiation Oncology 11/2013; 8(1):260. · 2.11 Impact Factor
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    ABSTRACT: 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. 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: www.drks.de Trial ID: DRKS00005127.
    Radiation Oncology 10/2013; 8(1):234. · 2.11 Impact Factor
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    ABSTRACT: For palliative care of spinal bone metastases, stability assessment is of crucial importance. Pathological fractures, instability-related patient immobility and the extent of bone metastasis have been reported to affect patient outcome and these parameters have therefore been used for treatment stratification. We report on stability-dependent fracture and survival rates in over 300 non-small cell lung cancer (NSCLC) patients. Data from 303 patients with 868 osteolytic metastases treated with radiotherapy (RT) between 2000 and 2012 were evaluated retrospectively. In NSCLC patients with bone metastases only, the retrospective 6- and 12-month overall survival (OS) rates were 76.7 and 47.2 %, respectively. In patients with additional non-bone distant metastases, these values were 60.0 and 34.0 %, respectively. Survival rates were significantly lower in patients with multiple bone metastases and in those suffering pathological fractures (p = 0.017). No significant impact of histological type, location of spinal lesions or treatment regime was detected. Furthermore, stability assessment revealed no influence of vertebral column stability on patient outcome (p = 0.739). Our analysis demonstrated a correlation between the pathological fractures of bone lesions, the number of bone metastases, additional distant metastases and survival. The results offer a rationale for future prospective investigations.
    Strahlentherapie und Onkologie 09/2013; · 4.16 Impact Factor
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    ABSTRACT: Treatment options for patients with locally advanced pancreatic cancer include surgery, chemotherapy as well as radiotherapy. In many cases, surgical resection is not possible, and therefore treatment alternatives have to be performed. Chemoradiation has been established as a convincing treatment alternative for locally advanced pancreatic cancer. Carbon ions offer physical and biological characteristics. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increased relative biological effectiveness (RBE), which can be calculated between 1.16 and 2.46 depending on the pancreatic cancer cell line as well as the endpoint analyzed. Japanese Data on the evaluation of carbon ion radiation therapy showed promising results for patients with pancreatic cancer.Methods and design: The present PHOENIX-01 trial evaluates carbon ion radiotherapy using the active rasterscanning technique in patients with advanced pancreatic cancer in combination with weekly gemcitabine and adjuvant gemcitabine. Primary endpoint is toxicity, secondary endpoints are overall survival, progression-free survival and response. The physical and biological properties of the carbon ion beam promise to improve the therapeutic ratio in patients with pancreatic cancer: Due to the inverted dose profile dose deposition in the entry channel of the beam leads to sparing of normal tissue; the Bragg peak can be directed into the defined target volume, and the sharp dose fall-off thereafter again spares normal tissue behind the target volume. The higher RBE of carbon ions, which has been shown also for pancreatic cancer cell lines in the preclinical setting, is likely to contribute to an increase in local control, and perhaps in OS. Early data from Japanese centers have shown promising results. In conclusion, this is the first trial to evaluate actively delivered carbon ion beams in patients with locally advanced pancreatic cancer within a dose-escalation strategy.Trial registration: NCT01795274.
    BMC Cancer 09/2013; 13(1):419. · 3.33 Impact Factor

Publication Stats

2k Citations
529.33 Total Impact Points

Institutions

  • 2005–2014
    • Universität Heidelberg
      • Department of Radiation Oncology
      Heidelburg, Baden-Württemberg, Germany
  • 2012
    • Nagoya City University
      • Department of Radiology (Hospital)
      Nagoya, Aichi, Japan
  • 2004–2007
    • German Cancer Research Center
      • Division of Medical Physics in Radiation Oncology
      Heidelberg, Baden-Wuerttemberg, Germany