Report on planning comparison of VMAT, IMRT and helical tomotherapy for the ESCALOX-trial pre-study.

BACKGROUND: The ESCALOX trial was designed as a multicenter, randomized prospective dose escalation study for head and neck cancer. Therefore, feasibility of treatment planning via different treatment planning systems (TPS) and radiotherapy (RT) techniques is essential. We hypothesized the comparability of dose distributions for simultaneous integrated boost (SIB) volumes respecting the constraints by different TPS and RT techniques. METHODS: CT data sets of the first six patients (all male, mean age: 61.3 years) of the pre-study (up to 77 Gy) were used for comparison of IMRT, VMAT, and helical tomotherapy (HT). Oropharynx was the primary tumor location. Normalization of the three step SIB (77 Gy, 70 Gy, 56 Gy) was D95% = 77 Gy. Coverage (CVF), healthy tissue conformity index (HTCI), conformation number (CN), and dose homogeneity (HI) were compared for PTVs and conformation index (COIN) for parotids. RESULTS: All RT techniques achieved good coverage. For SIB77Gy, CVF was best for IMRT and VMAT, HT achieved highest CN followed by VMAT and IMRT. HT reached good HTCI value, and HI compared to both other techniques. For SIB70Gy, CVF was best by IMRT. HTCI favored HT, consequently CN as well. HI was slightly better for HT. For SIB56Gy, CVF resulted comparably. Conformity favors VMAT as seen by HTCI and CN. Dmean of ipsilateral and contralateral parotids favor HT. CONCLUSION: Different TPS for dose escalation reliably achieved high plan quality. Despite the very good results of HT planning for coverage, conformity, and homogeneity, the TPS also achieved acceptable results for IMRT and VMAT. Trial registration ClinicalTrials.gov Identifier: NCT01212354, EudraCT-No.: 2010-021139-15. ARO: ARO 14-01.

The Expression of Checkpoint and DNA Repair Genes in Head and Neck Cancer as Possible Predictive Factors.

DNA damage response failure may influence the efficacy of DNA-damaging treatments. We determined the expression of 16 genes involved in distinct DNA damage response pathways, in association with the response to standard therapy. Twenty patients with locoregionally advanced, squamous cell head and neck carcinoma were enrolled. The treatment included induction chemotherapy (iChT) with docetaxel, cisplatin and 5-fluorouracil followed by concomitant chemoradiotherapy (ChRT) or radiotherapy (RT) alone. The volumetric metabolic therapeutic response was determined by [18F]FDG-PET/CT. In the tumor and matched normal tissues collected before treatment, the gene expressions were examined via the quantitative real-time polymerase chain reaction (qRT-PCR). The down-regulation of TP53 was apparently associated with a poor response to iChT, its up-regulation with complete regression in 2 cases. 7 cases with down-regulated REV1 expression showed complete regression after ChRT/RT, while 1 case with REV1 overexpression was resistant to RT. The overexpression of WRN was an independent predictor of tumor relapse. Our results suggest that an altered expression of REV1 predicts sensitivity to RT, while WRN overexpression is an unfavorable prognostic factor.

Volumetric response of intracranial meningioma after photon or particle irradiation.

BACKGROUND: Meningiomas are usually slow growing, well circumscribed intracranial tumors. In symptom-free cases observation with close follow-up imaging could be performed. Symptomatic meningiomas could be surgically removed and/or treated with radiotherapy. The study aimed to evaluate the volumetric response of intracranial meningiomas at different time points after photon, proton, and a mixed photon and carbon ion boost irradiation. PATIENTS AND METHODS: In Group A 38 patients received proton therapy (median dose: 56 GyE in 1.8-2 GyE daily fractions) or a mixed photon/carbon ion therapy (50 Gy in 2 Gy daily fractions with intensity modulated radiotherapy (IMRT) and 18 GyE in 3 GyE daily dose carbon ion boost). Thirty-nine patients (Group B) were treated by photon therapy with IMRT or fractionated stereotactic radiotherapy technique (median dose: 56 Gy in 1.8-2 Gy daily fractions). The delineation of the tumor volume was based on the initial, one- and two-year follow-up magnetic resonance imaging and these volumes were compared to evaluate the volumetric tumor response. RESULTS: Significant tumor volume shrinkage was detected at one- and at two-year follow-up both after irradiation by particles and by photons. No significant difference in tumor volume change was observed between photon, proton or combined photon plus carbon ion boost treated patients. WHO grade and gender appear to be determining factors for tumor volume shrinkage. CONCLUSION: Significant volumetric shrinkage of meningiomas could be observed independently of the applied radiation modality. Long-term follow-up is recommended to evaluate further dynamic of size reduction and its correlation with outcome data.

B-Cell-Based and Soluble Biomarkers in Body Liquids for Predicting Acute/Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main curative therapy for hematological malignancy such as leukemias, lymphomas, or multiple myelomas and some other hematological disorders. In this therapy, cure of hematological diseases relies on graft-versus-malignancy effects by allogenic immune cells. However, severe posttransplant treatment-associated complications such as acute graft-versus-host disease (aGvHD) and chronic graft-versus-host disease (cGvHD) limit this approach. Most research into GvHD has concentrated on the aGvHD, while the more complex and multifaceted chronic form has been largely poorly investigated. cGvHD is a multi-organ autoimmune disorder and is the major cause of non-relapse morbidity and mortality following allo-HSCT, occurring in about 50% of patients, or 13,000-15,000 patients per year worldwide. Therefore, there is a high medical need for an early prediction of these therapy-associated toxicities. Biomarkers have gained importance over the last decade in diagnosis, in prognosis, and in prediction of pending diseases or side effects. Biomarkers can be cells, factors isolated from target tissues, or soluble factors that can be detected in body fluids. In this review, we aim to summarize some of the recent developments of biomarkers in the field of allo-HSCT. We will focus on cell-based biomarkers (B-cell subsets) for cGvHD and soluble factors including microRNA (miRNA), which are excreted into serum/plasma and urine. We also discuss the potential role of cytosolic and extracellular 70 kDa heat shock proteins (HSP70) as potential biomarkers for aGvHD and their role in preclinical models. Proteomic biomarkers in the blood have been used as predictors of treatment responses in patients with aGvHD for many years. More recently, miRNAs have been found to serve as a biomarker to diagnose aGvHD in the plasma. Another development relates to urine-based biomarkers that are usually detected by capillary electrophoresis and mass spectrometry. These biomarkers have the potential to predict the development of severe aGvHD (grades III-IV), overall mortality, and the pending development of cGvHD in patients posttransplant.

Evaluation of the good tumor response of embryonal tumor with abundant neuropil and true rosettes (ETANTR).

The embryonal tumor with abundant neuropil and true rosettes is a rare and highly malignant variant of embryonal brain tumors. It usually affects infants and young children under the age of 4 years and exhibits a very aggressive course with a dismal prognosis. For the 68 cases reported to date the mean age at diagnosis was 25.42 months (range 3-57 months). Survival data are available for 48 children (including our case): the median overall survival is 13.0 months, though 6 (9%) of the children have had a relative long survival (>30 months). The aggressive combined treatment, involving primary surgical tumor removal, adjuvant polychemotherapy, including high-dose chemotherapy with stem cell transplantation, radiotherapy and radiochemotherapy, might play an important role in the longer survival. We have performed a literature review and we present here a multimodal-treated case of a 2- year-old girl with a long survival, who was reoperated when recurrence occurred. The residual tumor demonstrated a good response to temozolomide radiochemotherapy (craniospinal axis + boost) and followed by maintenance temozolomide. The described complex aggressive treatment option might be considered for future cases of this tumor entity.

Correlation of Hsp70 Serum Levels with Gross Tumor Volume and Composition of Lymphocyte Subpopulations in Patients with Squamous Cell and Adeno Non-Small Cell Lung Cancer.

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.

[Role of 18FDG-PET/CT in the management and gross tumor volume definition for radiotherapy of head and neck cancer; single institution experiences based on long-term follow-up]. / 18FDG-PET/CT szerepe fej-nyak daganatok kezelésében és a sugárterápiás tumortérfogat meghatározásában - Az SZTE Onkoterápiás Klinika eredményeinek értékelése.

The purpose of our work is evaluation of the impact of 18FDG-PET/CT on the complex management of locoregionally advanced (T3-4N1-3) head and neck squamous cell cancer (LAHNSC), and on the target definition for 3D conformal (3DCRT) and intensity-modulated radiotherapy (IMRT). 18FDG-PET/CT were performed on 185 patients with LAHNSC prior to radiotherapy/chemoradiation in the treatment position between 2006 and 2011. Prior to it 91 patients received induction chemotherapy (in 20 cases of these, baseline PET/CT was also available). The independently delineated CT-based gross tumor volume (GTVct) and PET/CT based ones (GTVpet) were compared. Impact of PET/CT on the treatment strategy, on tumor response evaluation to ICT, on GTV definition furthermore on overall and disease-specific survival (OS, DSS) was analysed. PET/CT revealed 10 head and neck, 2 lung cancers for 15 patients with carcinoma of unknown primary (CUP) while 3 remained unknown. Second tumors were detected in 8 (4.4%), distant metastasis in 15 (8.2%) cases. The difference between GTVct and GTVpet was significant (p=0.001). In 16 patients (14%) the GTVpet were larger than GTVct due to multifocal manifestations in the laryngo-pharyngeal regions (4 cases) or lymph node metastases (12 cases). In the majority of the cases (82 pts, 72%) PET/CT-based conturing resulted in remarkable decrease in the volume (15-20%: 4 cases, 20-50%: 46 cases, >50%: 32 cases). On the basis of the initial and post-ICT PET/CT comparison in 15/20 patients more than 50% volume reduction and in 6/20 cases complete response were achieved. After an average of 6.4 years of follow-up the OS (median: 18.3±2.6 months) and DSS (median: 25.0±4.0 months) exhibited close correlation (p=0.0001) to the GTVpet. In cases with GTVpet <10 cm3 prior to RT, DSS did not reach the median, the mean is 82.1±6.1 months, while in cases with GTVpet 10-40 cm3 the median of the DSS was 28.8±4.9 months (HR = 3.57; 95% CI: 1.5-8.3), and in those with GTVpet >40 cm3 the median DSS was 8.4±0.96 months (HR= 11.48; 95% CI: 5.3-24.9). Our results suggest that 18FDG-PET/CT plays an important role for patient with LAHNSC, by modifying the treatment concept and improving the target definition for selective RT modalities. Volumetric PET/CT-based assessment of the tumor response after ICT gives valuable contribution to further therapy planning.

Clinical course of central neurocytoma with malignant transformation-an indication for craniospinal irradiation.

Central neurocytoma is generally considered to be a benign tumor and the literature suggests that a cure may be attained by surgery ± adjuvant focal irradiation. However, there is a need for change in the therapeutic strategy for the subgroup of patients with aggressive central neurocytoma. An example case is presented and the literature on central neurocytoma cases with malignant features and dissemination via the cerebrospinal fluid is reviewed and the radiotherapeutic strategies available for central neurocytoma treatment is discussed. Nineteen cases including the present report with a malignant course and cerebrospinal fluid dissemination have been described to date, most of them involving an elevated MIB-1 labeling index. Our case exhibited atypical central neurocytoma with an initially elevated MIB-1 labeling index (25-30 %). The primary treatment included surgery and focal radiotherapy. Three years later the disease had disseminated throughout the craniospinal axis. A good tumor response and symptom relief were achieved with repeated radiation and temozolomide chemotherapy. Central neurocytoma with an initially high proliferation activity has a high tendency to spread via the cerebrospinal fluid. The chemo- and radiosensitivity of the tumor suggest a more aggressive adjuvant therapy approach. Cases with a potential for malignant transformation should be identified and treated appropriately, including irradiation of the entire neuroaxis and adjuvant chemotherapy may be considered.

Development of a small-animal focal brain irradiation model to study radiation injury and radiation-injury modifiers.

PURPOSE: Our aim was to establish an effective small-animal focal brain radiation model for research on brain injuries. MATERIAL AND METHODS: Groups of up to six rats were exposed to a range of doses from 120-40 Gy, at 10 intervals of a 6 MeV electron beam. Open-field motor functions and water maze learning-memory tests were performed after the irradiation at two-week intervals. Morphological changes were detected through repeated magnetic resonance imaging (MRI) monthly and were compared with the histopathological findings to determine if they predicted late microscopic changes. RESULTS: The development of necrosis proved to be dose-dependent. 120 Gy resulted in serious deterioration within 4 weeks in all rats. Localized necrosis in one hemisphere was detected 2 months after the irradiation with ≥ 70 Gy, and 3 months after 40-60 Gy consistent for all animals. The Morris water maze (MWM) tests proved to be the most sensitive tool for the early detection of a brain functional impairment. MRI screening provided useful information on the development of radiation necrosis, which defined the time point for histological examinations. CONCLUSIONS: The described method permits accurate dose delivery to a definite part in one hemisphere of the brain for six rats at a time. Following complex examinations, a dose of 40 Gy and a follow-up time of 4 months are proposed for investigations on neuroradiation modifiers.

Post-operative management of primary glioblastoma multiforme in patients over 60 years of age.

BACKGROUND AND PURPOSE: Optimal treatment for elderly patients with glioblastoma multiforme is not well defined. We evaluated the efficacy of post-operative radiotherapy with or without concomitant and/or adjuvant temozolomide in patient, aged > or = 60 years to assess survival and identify prognostic factors of survival. METHODS: A retrospective analysis of overall survival and progression-free survival in patients with newly diagnosed glioblastoma multiforme aged > or = 60 years treated with post-operative radiotherapy with or without temozolomide chemotherapy was conducted at our institutions. Prognostic factors were determined by univariate and multivariate analyses. RESULTS: Of 75 study participants (54.7% male; median age at first diagnosis, 65.1 years), 29 (38.7%) underwent gross total resection, whereas others underwent partial resection or biopsy only. All but 1 patient received radiotherapy. Twenty patients received concomitant temozolomic e only. Adjuvant temozolomide (1-50 cycles) was administered in 42 patients; 16 received > or = 6 cycles. Median overall survival was 10.3 months. One- and 2-year overall survival rates were 42.6% and 6.7%, respectively. Median progression-free survival was 4.1 months. Radiochemotherapy was generally well tolerated. Median overall survival was 15.3 and 29.6 months for patients who received 6-12 cycles and >12 cycles of adjuvant temozolomide, respectively. There were no significant differences in overall survival between age groups (60-64, 65-69, and > or = 70 years). Adjuvant temozolomide, Karnofsky performance status > or = 70, and additional surgery after progression were significant prognostic factors of longer overall survival (p<0.05). CONCLUSIONS: Radiochemotherapy, including > or = 6 cycles of adjuvant temozolomide, was safe and prolonged survival of glioblastoma patients aged > or = 60 years. Aggressive therapy should not be withheld from patients aged > or = 60 years with good performance status because of age.