Prospective study on dosimetric comparison of helical tomotherapy and 3DCRT for craniospinal irradiation - A single institution experience.

AIM: This prospective study aims to assess feasibility of helical tomotherapy (HT) for craniospinal irradiation (CSI) and perform dosimetric comparison of treatment plans for both HT and 3D conformal radiotherapy (3DCRT). BACKGROUND: CSI is a challenging procedure. Large PTV size requires field matching due to technical limitations of standard linear accelerators, which cannot irradiate such volumes as a single field. HT could help to avoid these limitations as irradiation of long fields is possible without field matching. MATERIALS AND METHODS: Three adults were enrolled from 2009 to 2010. All patients received radiochemotherapy. Treatment plans in prone position for 3DCRT and in supine position for HT were generated. The superior plan was used for patients' irradiation. Plans were compared with the application of DVH, Dx parameters - where x represents a percentage of the structure volume receiving a normalized dose and homogeneity index (HI). RESULTS: All patients received HT irradiation. The treatment was well tolerated. The HT plans resulted in a better dose coverage and uniformity in the PTV: HI were 5.4, 7.8, 6.8 for HT vs. 10.3, 6.6, 10.4 for 3DCRT. For most organs at risk (OARs), the D(V80) was higher for HT than for 3DCRT, whereas D(V5) was lower for HT. CONCLUSIONS: HT is feasible for CSI, and in comparison with 3DCRT it improves PTV coverage. HT reduces high dose volumes of OARs, but larger volumes of normal tissue receive low radiation dose. HT requires further study to establish correlations between dosimetrical findings and clinical outcomes, especially with regard to late sequelae of treatment.

Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Cilengitide is a selective αvß3 and αvß5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. METHODS: In this multicentre, open-label, phase 3 study, we investigated the efficacy of cilengitide in patients from 146 study sites in 25 countries. Eligible patients (newly diagnosed, histologically proven supratentorial glioblastoma, methylated MGMT promoter, and age ≥18 years) were stratified for prognostic Radiation Therapy Oncology Group recursive partitioning analysis class and geographic region and centrally randomised in a 1:1 ratio with interactive voice response system to receive temozolomide chemoradiotherapy with cilengitide 2000 mg intravenously twice weekly (cilengitide group) or temozolomide chemoradiotherapy alone (control group). Patients and investigators were unmasked to treatment allocation. Maintenance temozolomide was given for up to six cycles, and cilengitide was given for up to 18 months or until disease progression or unacceptable toxic effects. The primary endpoint was overall survival. We analysed survival outcomes by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00689221. FINDINGS: Overall, 3471 patients were screened. Of these patients, 3060 had tumour MGMT status tested; 926 patients had a methylated MGMT promoter, and 545 were randomly assigned to the cilengitide (n=272) or control groups (n=273) between Oct 31, 2008, and May 12, 2011. Median overall survival was 26·3 months (95% CI 23·8-28·8) in the cilengitide group and 26·3 months (23·9-34·7) in the control group (hazard ratio 1·02, 95% CI 0·81-1·29, p=0·86). None of the predefined clinical subgroups showed a benefit from cilengitide. We noted no overall additional toxic effects with cilengitide treatment. The most commonly reported adverse events of grade 3 or worse in the safety population were lymphopenia (31 [12%] in the cilengitide group vs 26 [10%] in the control group), thrombocytopenia (28 [11%] vs 46 [18%]), neutropenia (19 [7%] vs 24 [9%]), leucopenia (18 [7%] vs 20 [8%]), and convulsion (14 [5%] vs 15 [6%]). INTERPRETATION: The addition of cilengitide to temozolomide chemoradiotherapy did not improve outcomes; cilengitide will not be further developed as an anticancer drug. Nevertheless, integrins remain a potential treatment target for glioblastoma. FUNDING: Merck KGaA, Darmstadt, Germany.

Evaluation of results of linac-based radiosurgery for brain metastases from primary lung cancer.

AIM: The purpose of our review was to evaluate results of radiosurgery for patients with brain metastases from lung cancer. BACKGROUND: Lung cancer is the leading cause of death from cancer and the most common source of brain metastases. Radiosurgery allows the precise focal delivery of a high single radiation dose to brain metastases and results in high rates of local control. MATERIALS AND METHODS: 83 patients were treated between 2006 and 2008. We evaluated local control and outcome after radiosurgery and identified prognostic factors. RESULTS: Median survival in the whole group was 7.8 months from radiosurgery and 11 months from diagnosis. Median survival in classes I, II and III was 13.2, 8.2 and 2.2 months. For 94% of patients symptoms improved or stabilised at the first follow-up visit and this status did not change during 7.1 months. According to the univariate analysis, factors associated with improved survival included: RPA class 1 compared with RPA 2 and 3, RPA class 2 compared with RPA 3, KPS > 70, control of the primary disease, radiosurgery performed more than once, level of haemoglobin >7 mmol/1, absence of extracranial metastases, volume of the biggest lesion <11 cm(3). The multivariate analysis confirmed a significant influence on survival for the following factors: RPA class 1 as compared with RPA 3, KPS > 70, absence of extracranial metastases, multiplicity of radiosurgery. CONCLUSIONS: Stereotactic radiosurgery is a safe and effective treatment. It proved to be effective and safe in older patients. Selection of patients who are likely to benefit most should be based on prognostic factors. KPS proved to be the most important prognostic factor. In the RPA III group (patients with KPS < 70) survival time was similar to that achieved after symptomatic medical management.

Neural and Onconeural Autoantibodies and Blood-Brain Barrier Disruption Markers in Patients Undergoing Radiotherapy for High-Grade Primary Brain Tumour.

Radiotherapy (RT) plays a key role in brain tumours but can negatively impact functional outcomes and quality of life. The aim of this study was to analyse anti-neural and onconeural autoantibodies and markers of blood-brain barrier (BBB) disruption in patients with primary brain cancer undergoing RT. MATERIALS AND METHODS: A prospective study was conducted on 45 patients with a brain tumour scheduled for intensity-modulated radiotherapy. Assessments were performed at baseline, post-RT, and at three months. We measured serum levels of BBB disruption biomarkers and anti-neural, onconeural, and organ-specific antibodies. RESULTS: Antibodies against nucleosome antigens and neuronal surface antigens were detected in 85% and 3% of cases, respectively; anti-neural and onconeural antibodies were observed in 47% and 5.8%. In 44% patients, ≥2 antibody types were detected. No significant changes in BBB biomarkers were observed. CONCLUSION: The findings of this study show that a humoral immune response is common in patients undergoing RT for brain cancer. This response appears to be non-organ specific but rather directed against nucleosome antigens, but onconeural antibodies were uncommon, suggesting a low risk of a neurological paraneoplastic syndrome. Our data suggested that radiotherapy may not affect BBB integrity, but larger studies are needed to better characterise the pathophysiological effects of RT.

Rehabilitation Exercises Supported by Monitor-Augmented Reality for Patients with High-Grade Glioma Undergoing Radiotherapy: Results of a Randomized Clinical Trial.

BACKGROUND: Exercise has been shown to improve quality of life (QoL) and even treatment outcomes in cancer patients. However, the evidence to support the benefits of exercise in patients with high-grade glioma (HGG) is limited. Therefore, we performed a randomized clinical trial (RCT) to examine the effect of augmented-reality-based rehabilitation exercises on physical and functional fitness, cognitive function, fatigue, mood, QoL, selected blood parameters, brain derived neurotrophic factor (BDNF), and S100 protein in patients with HGG. METHODS: Adult patients with HGG scheduled to undergo radiotherapy after tumor resection were randomized to participate in an exercise program (experimental group, n = 25) or to receive usual care (controls, n = 22). Physical and mental fitness was measured at baseline, after the completion of radiotherapy, and at 3 months. The following tests were administered: Handgrip Strength Test; 6-Minute Walk Test; Time Up and Go test; Functional Independent Measure scale; Addenbrooke's Cognitive Examination III (ACE III); Hospital Anxiety and Depression Scale; Functional Cancer Therapy Assessment-Brain; and Functional Assessment of Chronic Illness Therapy-Fatigue. We also measured blood parameters, BDNF, and S100 protein levels. RESULTS: No significant changes were observed in the exercise group. However, the controls experienced a significant decrease in HGS and in the ACE III attention domain. No significant changes were observed in QoL, fatigue, BDNF, or S100 levels in either group. CONCLUSIONS: Augmented-reality-based exercise during radiation therapy may prevent loss of muscle strength and attention in patients with HGG.

Tomotherapy - a different way of dose delivery in radiotherapy.

AIM OF THE STUDY: Helical tomotherapy is one of the methods of radiotherapy. This method enables treatment implementation for a wide spectrum of clinical cases. The vast array of therapeutic uses of helical tomotherapy results directly from the method of dose delivery, which is significantly different from the classic method developed for conventional linear accelerators. The paper discusses the method of dose delivery by a tomotherapy machine. Moreover, an analysis and presentation of treatment plans was performed in order to show the therapeutic possibilities of the applied technology. Dose distributions were obtained for anaplastic medulloblastoma, multifocal metastases to brain, vulva cancer, tongue cancer, metastases to bones, and advanced skin cancer. Tomotherapy treatment plans were compared with conventional linear accelerator plans. RESULTS: Following the comparative analysis of tomotherapy and conventional linear accelerator plans, in each case we obtained the increase in dose distribution conformity manifested in greater homogeneity of doses in the radiation target area for anaplastic medulloblastoma, multifocal metastases to brain, vulva cancer, metastases to bones, and advanced skin cancer, and the reduction of doses in organs at risk (OAR) for anaplastic medulloblastoma, vulva cancer, tongue cancer, and advanced skin cancer. The time of treatment delivery in the case of a tomotherapy machine is comparable to the implementation of the plan prepared in intensity-modulated radiotherapy (IMRT) technique for a conventional linear accelerator. In the case of tomotherapy the application of a fractional dose was carried out in each case during one working period of the machine. For a conventional linear accelerator the total value of the fractional dose in the case of anaplastic medulloblastoma and metastases to bones was delivered using several treatment plans, for which a change of set-up was necessary during a fraction. CONCLUSION: The obtained results confirm that tomotherapy offers the possibility to obtain precise treatment plans together with the simplification of the therapeutic system.

Psychological Characteristics Associated with Post-Treatment Physical Status and Quality of Life in Patients with Brain Tumor Undergoing Radiotherapy.

Radiotherapy (RT) is a mainstay of treatment for brain tumors. To minimize the risk of side effects while maximizing the therapeutic effects, personalized treatment plans, consisting mainly of genomics, radiomics, and mathematical modeling, are increasingly being used. We hypothesize that personality characteristics could influence treatment outcomes and thus could be used to help personalize RT. Therefore, the aim of this study was to identify the psychological characteristics associated with post-treatment physical status and quality of life (QoL) in patients with brain tumors undergoing RT. Two psychological tests-the Eysenck Personality Questionnaire and the State-Trait Anxiety Inventory-were administered prior to RT. Physical parameters before and after RT were also assessed through the following tests: hand grip strength, Timed Up and Go test, 6 Min Walk Test, and Functional Independence Measure. The Functional Assessment of Cancer Therapy-General (FACT-G) was used to assess QoL. The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) was administered to assess fatigue. Neuroticism was significantly associated with low FACT-G Physical Well-Being scores. Psychoticism was associated with an improvement in physical fitness scores after RT. These findings suggest that personality traits should be considered when designing a personalized radiotherapy plan.

CGB and GNRH1 expression analysis as a method of tumor cells metastatic spread detection in patients with gynecological malignances.

BACKGROUND: Metastasis is a common feature of many advanced stage cancers and metastatic spread is thought to be responsible for cancer progression. Most cancer cells are localized in the primary tumor and only a small population of circulating tumor cells (CTC) has metastatic potential. CTC amount reflects the aggressiveness of tumors, therefore their detection can be used to determine the prognosis and treatment of cancer patients.The aim of this study was to evaluate human chorionic gonadotropin beta subunit (CGB) and gonadoliberin type 1 (GNRH1) expression as markers of tumor cells circulating in peripheral blood of gynecological cancer patients, indicating the metastatic spread of tumor. METHODS: CGB and GNRH1 expression level in tumor tissue and blood of cancer patients was assessed by real-time RT-PCR. The data was analyzed using the Mann-Whitney U and Spearman tests. In order to distinguish populations with homogeneous genes' expression the maximal likelihood method for one- and multiplied normal distribution was used. RESULT: Real time RT-PCR results revealed CGB and GNRH1 genes activity in both tumor tissue and blood of gynecological cancers patients. While the expression of both genes characterized all examined tumor tissues, in case of blood analysis, the transcripts of GNRH1 were found in all cancer patients while CGB were present in 93% of patients. CGB and GNRH1 activity was detected also in control group, which consisted of tissue lacking cancerous changes and blood of healthy volunteers. The log-transformation of raw data fitted to multiplied normal distribution model showed that CGB and GNRH1 expression is heterogeneous and more than one population can be distinguished within defined groups.Based on CGB gene activity a critical value indicating the presence of cancer cells in studied blood was distinguished. In case of GNRH1 this value was not established since the results of the gene expression in blood of cancer patients and healthy volunteers were overlapping. However one subpopulation consists of cancer patient with much higher GNRH1 expression than in control group was found. CONCLUSIONS: Assessment of CGB and GNRH1 expression level in cancer patients' blood may be useful for indicating metastatic spread of tumor cells.

Come and say what you think: reducing employees' self-censorship through procedural and interpersonal justice.

BACKGROUND: Self-censorship in an organization may be defined as a conscious decision by employees to refrain from expressing opinions, criticism or suggestions in situations of perceived irregularities. There are at least two reasons for this decision: firstly, the fear that speaking up would prompt negative consequences, and secondly, the belief that it would not bring about a change in the situation. Procedural justice in an organization may encourage employees to limit that silence, thereby diminishing fear and undermining the belief that change is impossible. PARTICIPANTS AND PROCEDURE: A set of three studies (total number of participants N = 710) was conducted in order to determine whether procedural justice predicts self-censorship and also to define the role of interpersonal justice in this relationship. It was assumed that procedural justice, while useful in the formation of an impartial and rigid legal system within an organization, is constrained by its disregard for personal relations. RESULTS: It was found that when employees perceive a work environment as providing influence over procedures, they declare less self-censorship motivated by fear and resignation. In high interpersonal justice conditions the role of procedural justice in predicting employee self-censorship as well as employee silence beliefs increases. CONCLUSIONS: Both fair treatment of all employees and the contextual and need-centered nature of such treatment should be integrated if self-censorship is to be reduced. The results confirm this conclusion for self-censorship (decision) and employee silence beliefs (belief that relations within the organization do not encourage people to speak up).

Significance of BRCA1 expression in breast and ovarian cancer patients with brain metastasis - A multicentre study.

PURPOSE: Cerebral metastases develop in 10-30% of patients with breast cancer (BC) and in around 3.3 to 4% of patients with ovarian cancer (OC). The aim of the multicenter study is to investigate the correlation between the expression of estrogen alpha receptors (ERα), progesterone receptors (PR), human epidermal growth factor receptor 2 (HER2), stromal cell-derived factor 1 (SDF1) and its receptor C-X-C chemokine receptor type 4 (CXCR4), breast cancer metastasis suppressor 1 (BRMS1), astrocyte elevated gene 1 (AEG1), depending on the status of BRCA1 protein, in patients suffering from OC and BC with brain metastases. PATIENTS AND METHODS: The analysis included 51 patients: 29 with BC and 22 with OC, in whom brain metastases were disclosed. RESULTS: In most patients (65.5% of BC patients and 68.2% of patients with OC tumors) BRCA1 protein loss was found. No correlation was disclosed between the levels of ERα, PR receptors, HER2, SDF1, CXCR4, AEG1, BRMS1 and BRCA1 status, patient age, stage of disease advancement, grade of histological maturity of the cells, presence of metastases to lymph nodes. A statistically significant correlation was disclosed between the negative expression of PR receptors and a high expression of CXCR4 in patients with BC. High values of the AEG1 protein (linked to metastases) were detected alongside a high expression of BRMS1 (a suppressor of metastases). CONCLUSIONS: Patients with BC and OC and brain metastases have a frequent loss of BRCA1 expression. The role of ERα, PR, HER2, SDF1, CXCR4, AEG1, BRMS1 in metastatic process needs further studies.