Carsten Nieder

Bio: Carsten Nieder is an academic researcher from Technische Universität München. The author has contributed to research in topics: Radiation therapy & Lung cancer. The author has an hindex of 24, co-authored 76 publications receiving 2692 citations. Previous affiliations of Carsten Nieder include Ludwig Maximilian University of Munich.

Reirradiation of recurrent high-grade gliomas using amino acid PET (SPECT)/CT/MRI image fusion to determine gross tumor volume for stereotactic fractionated radiotherapy.

Abstract: Purpose: To develop a valid treatment strategy for recurrent high-grade gliomas using stereotactic hypofractionated reirradiation based on biologic imaging and temozolomide. Patients and Methods: The trial included a total of 44 patients with recurrent high-grade gliomas (1 patient with anaplastic oligodendroglioma, 8 with anaplastic astrocytoma, 33 with glioblastoma multiforme, and 2 with gliosarcoma) after previous surgery and postoperative conventional radiotherapy ± chemotherapy. For fractionated stereotactic radiotherapy (SFRT) treatment planning, the gross tumor volume was defined by 11 C-methionine positron emission tomography (MET-PET) or 123 I-α-methyl-tyrosine (IMT) single-photon computed emission tomography (SPECT)/computed tomography (CT)/magnetic resonance imaging (MRI) fusion in 82% of the patients and by CT/T1+gadolinium-MRI image fusion in 18% of the patients. Six fractions of 5 Gy were administered in 6 days. In 29 of 44 patients (66%), chemotherapy with temozolomide (200 mg/m 2 body surface/day) was given in one to two cycles before and four to five cycles after SFRT. The patients were evaluated in follow-up by clinical investigators and MRI or CT every 3 months after SFRT until death. In cases suspicious for radiation necrosis, a MET-PET or IMT-SPECT investigation was performed. Results: The median survival time in the whole group was 8 months. Treatment planning based on PET(SPECT)/CT/MRI imaging was associated with improved survival in comparison to treatment planning using CT/MRI alone: median survival time 9 months vs. 5 months ( p = 0.03, log–rank). Median survival time were 11 months for patients who received SFRT based on biologic imaging plus temozolomide and significantly lower, 6 months for patients treated with SFRT without biologic imaging, without temozolomide or without both ( p = 0.008, log rank). The most important prognostic factor in univariate analysis was a long interval between initial diagnosis and recurrence ( p = 0.0002, log–rank). In the multivariate model, time interval to retreatment ( p = 0.006) and temozolomide ( p = 0.04) remained statistically significant. No acute neurologic toxicity Grade 3 or higher and no Grade 4 hematologic toxicity was observed. Conclusion: This is the first study of biologic imaging optimized SFRT plus temozolomide in recurrent high-grade gliomas. It demonstrates the feasibility and safety of this approach. The most striking result of the trial is the statistically significant longer survival time in the univariate analysis for patients reirradiated using MET-PET or IMT-SPECT/CT/MRI image fusion in the treatment planning, in comparison to patients treated based on MRI/CT alone. Multivariate analysis confirmed a significant survival benefit from multimodal treatment (i.e., addition of temozolomide), despite the limited number of patients. Whether treatment planning with SPECT/PET independently influences survival has to be studied in a larger series of patients.

L-(methyl-11C) methionine positron emission tomography for target delineation in resected high-grade gliomas before radiotherapy.

Abstract: Purpose: Using magnetic resonance imaging (MRI), residual tumor cannot be differentiated from nonspecific postoperative changes in operated patients with brain gliomas. The higher specificity and sensitivity of l-(methyl-11C)-labeled methionine positron emissions tomography (MET-PET) in gliomas has been demonstrated in previous studies and is the rationale for the integration of this investigation in gross tumor volume delineation. The goal of this trial was to quantify the affect of MET-PET vs. with MRI in gross tumor volume definition for radiotherapy planning of high-grade gliomas. Methods and Materials: The trial included 39 patients with resected malignant gliomas. MRI and MET-PET data were coregistered based on mutual information. The residual tumor volume on MET-PET and the volume of tissue abnormalities on T 1 -weighted MRI (gadolinium [Gd] enhancement) and T 2 -weighted MRI (hyperintensity areas) were compared using MET-PET/MRI fusion images. Results: The MET-PET vs. Gd-enhanced T 1 -weighted MRI analysis was performed on 39 patients. In 5 patients (13%), MET uptake corresponded exactly with Gd enhancement, and in 29 (74%) of 39 patients, the region of MET uptake was larger than that of the Gd enhancement. In 27 (69%) of the 39 patients, the Gd enhancement area extended beyond the MET enhancement. MET uptake was detected up to 45 mm beyond the Gd enhancement. MET-PET vs. T 2 -weighted MRI was investigated in 18 patients. MET uptake did not correspond exactly with the hyperintensity areas on T 2 -weighted MRI in any patient. In 9 (50%) of 18 patients, MET uptake extended beyond the hyperintensity area on the T 2 -weighted MRI, and in 18 (100%), at least some hyperintensity on the T 2 -weighted MRI was located outside the MET enhancement area. MET uptake was detected up to 40 mm beyond the hyperintensity area on T 2 -weighted MRI. Conclusion: In operated patients with brain gliomas, the size and location of residual MET uptake differs considerably from abnormalities found on postoperative MRI. Because postoperative changes cannot be differentiated from residual tumor by MRI, MET-PET, with a greater specificity for tumor tissue, can help to outline the gross tumor volume with greater accuracy.

An interindividual comparison of O-(2-[18F]fluoroethyl)-L-tyrosine (FET)- and L-[methyl-11C]methionine (MET)-PET in patients with brain gliomas and metastases.

Abstract: Purpose L-[methyl- 11 C]methionine (MET)–positron emission tomography (PET) has a high sensitivity and specificity for imaging of gliomas and metastatic brain tumors. The short half-life of 11 C (20 minutes) limits the use of MET-PET to institutions with onsite cyclotron. O-(2- [ 18 F]fluoroethyl)-L-tyrosine (FET) is labeled with 18 F (half-life, 120 minutes) and could be used much more broadly. This study compares the uptake of FET and MET in gliomas and metastases, as well as treatment-induced changes. Furthermore, it evaluates the gross tumor volume (GTV) of gliomas defined on PET and magnetic resonance imaging (MRI). Methods and Materials We examined 42 patients with pretreated gliomas (29 patients) or brain metastases (13 patients) prospectively by FET- and MET-PET on the same day. Uptake of FET and MET was quantified by standardized uptake values. Imaging contrast was assessed by calculating lesion–to–gray matter ratios. Tumor extension was quantified by contouring GTV in 17 patients with brain gliomas. Gross tumor volume on PET was compared with GTV on MRI. Sensitivity and specificity of MET- and FET-PET for differentiation of viable tumor from benign changes were evaluated by comparing the PET result with histology or clinical follow-up. Results There was a strong linear correlation between standardized uptake values calculated for both tracers in cortex and lesions: r = 0.78 ( p = 0.001) and r = 0.84 ( p Conclusions O-(2- [ 18 F]fluoroethyl)-L-tyrosine–PET and MET-PET provide comparable diagnostic information on gliomas and brain metastases. Like MET-PET, FET-PET can be used for differentiation of residual or recurrent tumor from treatment-related changes/pseudoprogression, as well as for delineation of gliomas.

Update of human spinal cord reirradiation tolerance based on additional data from 38 patients

Abstract: Purpose: To update a combined analysis of all published clinical data. Methods and Materials: We collected data from 38 additional patients treated in our department or published in four different reports and calculated the biologically effective dose (BED) according to the linear-quadratic model using an α/β value of 2 Gy for cervical and thoracic cord and 4 Gy for lumbar cord. In this model, a dose of 50 Gy given in single daily fractions of 2 Gy is equivalent to a BED of 100 Gy 2 or 75 Gy 4 . Results: The 2005 risk score based on three variables (cumulative BED, highest BED of all treatment series in a particular individual, and interval), which discriminate three different risk groups, does not require modification. The low-risk group now contains 1 case of radiation myelopathy (RM) after hypofractionated stereotactic reirradiation. Therefore, the rate increased from 0% to 3%. Intermediate-risk patients developed RM in 25%, and high-risk patients in 90%. When the interval between the two treatment courses is not shorter than 6 months and the dose of each course is ≤98 Gy 2 , the cumulative BED where no case of RM has yet been reported is 120 Gy 2 . Conclusions: Based on these updated results, the risk of RM appears small after ≤135.5 Gy 2 when the interval is not shorter than 6 months and the dose of each course is ≤98 Gy 2 . We would recommend limiting the dose to the lowest feasible level. The influence of very steep dose gradients from stereotactic and intensity-modulated approaches (i.e., a more complex volume-effect) requires further evaluation.

Cervical lymph node metastases from occult squamous cell carcinoma: cut down a tree to get an apple?

Abstract: Purpose: To review the value of extended diagnostic work-up procedures and to compare the results of comprehensive or volume-restricted radiotherapy in patients presenting with cervical lymph node metastases from clinically undetectable squamous cell carcinoma. Methods and Materials: A systematic review was undertaken of published papers up to May 2000. Results: Positron emission tomography (PET) has an overall staging accuracy of 69%, with a positive predictive value of 56% and negative predictive value of 86%. With negative routine clinical examination and computerized tomography (CT) or magnetic resonance imaging (MRI), PET detected primary tumors in 5–25% of patients, whereas ipsilateral tonsillectomy discovered carcinoma in about 25% of patients. Laser-induced fluorescence imaging with panendoscopy and directed biopsies showed some encouraging preliminary results and warrants further study. All together, the reported mucosal carcinoma emergence rates were 2–13% (median, 9.5%) after comprehensive radiotherapy and 5–44% (median, 8%) after unilateral neck irradiation. The corresponding nodal relapse rates were 8–45% (median, 19%) and 31–63% (median, 51.5%), and 5-year survival rates were 34–63% (median, 50%) and 22–41% (median, 36.5%), respectively. Retrospective single-institution comparisons between comprehensive and unilateral neck radiotherapy did not show apparent differences in outcome. Prognostic determinants for survival are the N stage, number of nodes, extracapsular extension, and histologic grade. No data were found to support the benefit of chemotherapy in this disease. Conclusion: Physical examination, CT or MRI, and panendoscopy with biopsies remain the standard work-up for these patients. Routine use of PET or laser-induced fluorescence imaging cannot be firmly advocated based on presently available data. Although combination of nodal dissection with comprehensive radiotherapy yielded most favorable results, its impact on the quality of life should be recognized, and the confounding effects of patient selection for various treatment modalities on therapeutic outcome cannot be ruled out. A randomized trial comparing the therapeutic value of comprehensive vs. volume-limited radiotherapy is being considered.

Stereotactic body radiation therapy: The report of AAPM Task Group 101

Abstract: Task Group 101 of the AAPM has prepared this report for medical physicists, clinicians, and therapists in order to outline the best practice guidelines for the external-beam radiation therapy technique referred to as stereotactic body radiation therapy (SBRT). The task group report includes a review of the literature to identify reported clinical findings and expected outcomes for this treatment modality. Information is provided for establishing a SBRT program, including protocols, equipment, resources, and QA procedures. Additionally, suggestions for developing consistent documentation for prescribing, reporting, and recording SBRT treatment delivery is provided.

Bevacizumab Plus Irinotecan in Recurrent Glioblastoma Multiforme

Abstract: Purpose The prognosis for patients with recurrent glioblastoma multiforme is poor, with a median survival of 3 to 6 months. We performed a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan. Patients and Methods This phase II trial included two cohorts of patients. The initial cohort, comprising 23 patients, received bevacizumab at 10 mg/kg plus irinotecan every 2 weeks. The dose of irinotecan was based on the patient’s anticonvulsant: Patients taking enzyme-inducing antiepileptic drugs (EIAEDs) received 340 mg/m 2 , and patients not taking EIAEDs received 125 mg/m 2 . After this regimen was deemed safe and effective, the irinotecan schedule was changed to an accepted brain tumor regimen of four doses in 6 weeks, in anticipation of a phase III randomized trial of irinotecan versus irinotecan and bevacizumab. The second cohort, comprising 12 patients, received bevacizumab 15 mg/kg every 21 days and irinotecan on days 1, 8, 22, and 29. Each cycle was 6 weeks long and concluded with patient evaluations, including magnetic resonance imaging. Results The 6-month progression-free survival among all 35 patients was 46% (95% CI, 32% to 66%). The 6-month overall survival was 77% (95% CI, 64% to 92%). Twenty of the 35 patients (57%; 95% CI, 39% to 74%) had at least a partial response. One patient developed a CNS hemorrhage, which occurred in his 10th cycle. Four patients developed thromboembolic complications (deep venous thrombosis and/or pulmonary emboli). Conclusion Bevacizumab and irinotecan is an effective treatment for recurrent glioblastoma multiforme and has moderate toxicity. J Clin Oncol 25:4722-4729. © 2007 by American Society of Clinical Oncology

Ovarian cancer: strategies for overcoming resistance to chemotherapy

Abstract: Ovarian cancer is responsible for 4% of deaths from cancer in women. Treatment comprises a combination of surgery and chemotherapy, but patients typically experience disease relapse within 2 years of the initial treatment. Further treatment can extend survival, although relapse eventually occurs again. A better understanding of the mechanisms that underlie this drug resistance should allow treatment to be optimized, so that substantial improvements in the outlook for women with this disease can be achieved.

ICRP PUBLICATION 118: ICRP Statement on Tissue Reactions and Early and Late Effects of Radiation in Normal Tissues and Organs – Threshold Doses for Tissue Reactions in a Radiation Protection Context

Abstract: This report provides a review of early and late effects of radiation in normal tissues and organs with respect to radiation protection. It was instigated following a recommendation in Publication 103 (ICRP, 2007), and it provides updated estimates of 'practical' threshold doses for tissue injury defined at the level of 1% incidence. Estimates are given for morbidity and mortality endpoints in all organ systems following acute, fractionated, or chronic exposure. The organ systems comprise the haematopoietic, immune, reproductive, circulatory, respiratory, musculoskeletal, endocrine, and nervous systems; the digestive and urinary tracts; the skin; and the eye. Particular attention is paid to circulatory disease and cataracts because of recent evidence of higher incidences of injury than expected after lower doses; hence, threshold doses appear to be lower than previously considered. This is largely because of the increasing incidences with increasing times after exposure. In the context of protection, it is the threshold doses for very long follow-up times that are the most relevant for workers and the public; for example, the atomic bomb survivors with 40-50years of follow-up. Radiotherapy data generally apply for shorter follow-up times because of competing causes of death in cancer patients, and hence the risks of radiation-induced circulatory disease at those earlier times are lower. A variety of biological response modifiers have been used to help reduce late reactions in many tissues. These include antioxidants, radical scavengers, inhibitors of apoptosis, anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, growth factors, and cytokines. In many cases, these give dose modification factors of 1.1-1.2, and in a few cases 1.5-2, indicating the potential for increasing threshold doses in known exposure cases. In contrast, there are agents that enhance radiation responses, notably other cytotoxic agents such as antimetabolites, alkylating agents, anti-angiogenic drugs, and antibiotics, as well as genetic and comorbidity factors. Most tissues show a sparing effect of dose fractionation, so that total doses for a given endpoint are higher if the dose is fractionated rather than when given as a single dose. However, for reactions manifesting very late after low total doses, particularly for cataracts and circulatory disease, it appears that the rate of dose delivery does not modify the low incidence. This implies that the injury in these cases and at these low dose levels is caused by single-hit irreparable-type events. For these two tissues, a threshold dose of 0.5Gy is proposed herein for practical purposes, irrespective of the rate of dose delivery, and future studies may elucidate this judgement further.

PI3K/AKT/mTOR Pathway in Angiogenesis

Abstract: The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is activated in the majority of human cancers. This pathway is known to play a key role in numerous cellular functions including proliferation, adhesion, migration, invasion, metabolism, and survival, but in the current review we focus on its role in angiogenesis. PI3K activation may occur via RAS mutation, loss of phosphatase and tensin homolog (PTEN), or by increased expression of growth factor receptors such as epidermal growth factor receptor. There is a connection between the PI3K pathway and angiogenesis. Hypoxia leads to HIF-1α stabilization and is a major stimulus for increased vascular endothelial growth factor (VEGF) production by tumor cells. However, activation of the PI3K/AKT pathway in tumor cells can also increase VEGF secretion, both by hypoxia-inducible factor 1 (HIF-1) dependent and independent mechanisms. The PI3K/AKT pathway also modulates the expression of other angiogenic factors such as nitric oxide and angiopoietins. Numerous inhibitors targeting the PI3K/AKT/mTOR pathway have been developed, and these agents have been shown to decrease VEGF secretion and angiogenesis. The effect of these inhibitors on tumor vasculature can be difficult to predict. The vasculature of tumors is aberrant, leading to sluggish bloodflow and elevated interstitial blood pressure, which can be perpetuated by the high levels of VEGF. Hence, decreasing VEGF expression can paradoxically lead to vascular normalization and improved bloodflow in some tumors. In addition to its importance in cancer, the PI3K pathway also plays an essential role in the formation of normal blood vessels during development. Embryos with kinase-dead p110α catalytic subunit of PI3K develop vascular defects. Stimulation of endothelial cells by VEGF leads to activation of the PI3K pathway within these cells, which is important for cell migration. Sustained endothelial activation of AKT1 has been shown to induce the formation of structurally abnormal blood vessels that recapitulate the aberrations of tumor vessels. Hence, the PI3K pathway plays an important role in regulating angiogenesis both in normal tissues and in cancers.