Regional deep hyperthermia in combination with whole brain radiotherapy (WBRT) in poor prognosis patients with brain metastases.

PURPOSE: The aim of this study is to assess for the first time, the role of regional deep hyperthermia in combination with radiotherapy and systemic therapy in patients with poor prognosis of brain metastases (GPI ≤ 2.5). METHODS: Patients with confirmed cerebral metastases and classified as GPI score ≤ 2.5 were included in this prospective study. Pretreatment stratification was defined as patients with 0-1 GPI score (Group A) and patients with 1.5-2.5 GPI score (Group B). HT was applied twice a week, 60 min per session, during RT by regional capacitive device (HY-DEEP 600WM system) at 13.56 MHz radiofrequency. RESULTS: Between June 2015 and June 2017, 15 patients and a total of 49 brain metastases were included in the protocol. All patients received all HT sessions as planned. RT and systemic therapy were also completed as prescribed. Tolerance to treatment was excellent and no toxicity was registered. Patients with HT effective treatment time longer than the median (W90time > 88%) showed better actuarial PFS at 6 and 12 months (100% and 66.7%, respectively) compared to those with less HT effective treatment time (50% and 0%, respectively) (p < 0.031). Median OS was 6 months (range 1-36 months). Stratification by GPI score showed a median OS of 3 months (CI 95% 2.49-3.51) in Group A and 8.0 months (CI 95% 5.15-10.41) in Group B (p = 0.035). CONCLUSIONS: Regional hyperthermia is a feasible and safe technique to be used in combination with RT in brain metastases patients, improving PFS and survival in poor prognostic brain metastasis patients.

Sparing the hippocampus and the hypothalamic- pituitary region during whole brain radiotherapy: a volumetric modulated arc therapy planning study.

BACKGROUND: Feasibility testing of a simultaneous sparing approach of hippocampus, hypothalamus and pituitary gland in patients undergoing whole-brain radiotherapy (WBRT) with and without a concomitant boost to metastatic sites. INTRODUCTION: Cognitive impairment and hormonal dysfunction are common side effects of cranial radiotherapy. A reduced dose application to the patho-physiologically involved functional brain areas, i.e. hippocampus, hypothalamus and pituitary gland, could reduce these common side effects. While hippocampal sparing is already a common practice to improve cognitive outcome, technical experience of additional combined sparing of the hypothalamus/pituitary gland (HT-P) is insufficient. METHODS: Twenty patients were included in the planning study. In 11 patients, a total dose of 36 Gy of WBRT (2 Gy per fraction) plus a simultaneous integrated boost (SIB) of 9 Gy (0.5 Gy per fraction, total dose: 45 Gy) to the brain metastases was applied. In 9 patients, prophylactic cranial irradiation (PCI) was simulated with a total dose of 30 Gy (2 Gy per fraction). In both patient cohorts, a sparing approach of the hippocampus and the HT-P area was simulated during WBRT. For all treatment plans, volumetric modulated arc therapy (VMAT) was used. Quality assurance included assessment of homogeneity, conformality and target coverage. RESULTS: The mean dose to the hippocampus and HT-P region was limited to less than 50% of the prescribed dose to the planning target volume (PTV) in all treatment plans. Dose homogeneity (HI) of the target volume was satisfying (median HI = 0.16 for WBRT+SIB and 0.1 for PCI) and target coverage (conformation number, CN) was not compromised (median CN = 0.82 for SIB and 0.86 for PCI). CONCLUSION: Simultaneous dose reduction to the hippocampus and the HT-P area did not compromise the PTV coverage in patients undergoing WBRT+SIB or PCI using VMAT. While the feasibility of the presented approach is promising, prospective neurologic, endocrine outcome and safety studies are required.

Is prophylactic cranial irradiation necessary in individuals suffering from surgically resected pT1-2N0M0 small cell lung cancer?

Adjuvant chemotherapeutics and prophylactic cranial irradiation (PCI) are both recommended in the National Comprehensive Cancer Network (NCCN) guidelines for treating individuals suffering from surgically resected pT1-2N0M0 small cell lung cancer (SCLC). Whether adjuvant chemotherapy combined with PCI is superior to adjuvant chemotherapy alone in these patients is largely unknown. PCI may therefore be with uncertain effects in surgically resected pT1-2N0M0 SCLC.

Endocrine Deficiency As a Function of Radiation Dose to the Hypothalamus and Pituitary in Pediatric and Young Adult Patients With Brain Tumors.

PURPOSE: There are sparse data defining the dose response of radiation therapy (RT) to the hypothalamus and pituitary in pediatric and young adult patients with brain tumors. We examined the correlation between RT dose to these structures and development of endocrine dysfunction in this population. MATERIALS AND METHODS: Dosimetric and clinical data were collected from children and young adults (< 26 years of age) with brain tumors treated with proton RT on three prospective studies (2003 to 2016). Deficiencies of growth hormone (GH), thyroid hormone, adrenocorticotropic hormone, and gonadotropins were determined clinically and serologically. Incidence of deficiency was estimated using the Kaplan-Meier method. Multivariate models were constructed accounting for radiation dose and age. RESULTS: Of 222 patients in the study, 189 were evaluable by actuarial analysis, with a median follow-up of 4.4 years (range, 0.1 to 13.3 years), with 31 patients (14%) excluded from actuarial analysis for having baseline hormone deficiency and two patients (0.9%) because of lack of follow-up. One hundred thirty patients (68.8%) with medulloblastoma were treated with craniospinal irradiation (CSI) and boost; most of the remaining patients (n = 56) received involved field RT, most commonly for ependymoma (13.8%; n = 26) and low-grade glioma (7.4%; n = 14). The 4-year actuarial rate of any hormone deficiency, growth hormone, thyroid hormone, adrenocorticotropic hormone, and gonadotropin deficiencies were 48.8%, 37.4%, 20.5%, 6.9%, and 4.1%, respectively. Age at start of RT, time interval since treatment, and median dose to the combined hypothalamus and pituitary were correlated with increased incidence of deficiency. CONCLUSION: Median hypothalamic and pituitary radiation dose, younger age, and longer follow-up time were associated with increased rates of endocrinopathy in children and young adults treated with radiotherapy for brain tumors.

Prophylactic Cranial Irradiation in Extensive Stage Small Cell Lung Cancer: Outcomes at a Comprehensive Cancer Centre.

PURPOSE: The role of prophylactic cranial irradiation (PCI) remains controversial in extensive stage small cell lung cancer (ES-SCLC) with the publication of 2 randomized control trials demonstrating differing outcomes in overall survival. The aim of this study is to determine the impact of PCI on survival and the development of brain metastasis while addressing the disparate use of postchemotherapy brain imaging in the aforementioned trials. METHODS AND MATERIALS: The medical records of 397 consecutive patients with ES-SCLC between Jan. 1, 2005 and Dec. 31, 2011 were retrospectively reviewed. In those eligible patients (n = 155) without baseline brain metastases and who had at least a partial response to chemotherapy, overall survival and time to brain metastasis were estimated using the Kaplan-Meier method comparing patients receiving PCI or not, using both univariate and multivariate analyses. Patients were stratified by their receipt of initial postchemotherapy brain imaging. Follow-up did not include serial brain imaging, which was performed when clinically indicated. Differences between the groups with covariates were analyzed using χ2 statistics and Student's t-tests. RESULTS: By multivariate analysis, statistically significant predictors of overall survival were the presence of extrathoracic metastases, performance status and use of PCI. There was a statistically significant difference in overall survival (HR 0.55; 95% CI: 0.39-0.77; P = .0005) and time to brain metastasis (HR 0.40; 95% CI: 0.23-0.66; P = .0004) with the use of PCI. Median survival for the PCI and non-PCI groups was 13.5 and 8.5 months respectively. A survival difference with PCI was observed in both patients that received postchemotherapy brain imaging (HR 0.55; 95% CI: 0.35-0.88; P = .012) and those who did not (HR 0.48; 95% CI: 0.29-0.77; P = .0025). CONCLUSIONS: PCI in the setting of at least a partial response to chemotherapy was found to have a survival benefit and prolongation of the time to development of brain metastases, when factoring in the use of initial postchemotherapy but not routine surveillance brain imaging.

Whole-Brain Radiotherapy for Brain Metastases: Evolution or Revolution?

An estimated 20% of patients with cancer will develop brain metastases. Approximately 200,000 individuals in the United States alone receive whole-brain radiotherapy (WBRT) each year to treat brain metastases. Historically, the prognosis of patients with brain metastases has been poor; however, with new therapies, this is changing. Because patients are living longer following the diagnosis and treatment of brain metastases, there has been rising concern about treatment-related toxicities associated with WBRT, including neurocognitive toxicity. In addition, recent clinical trials have raised questions about the use of WBRT. To better understand this rapidly changing landscape, this review outlines the treatment roles and toxicities of WBRT and alternative therapies for the management of brain metastases.

[Use of hypnosis in radiotherapy as an alternative to general anesthesia in pediatric radiation oncology]. / Radiothérapie des enfants de moins de cinq ans : peut-on limiter les anesthésies itératives par les rituels et l'hypnose ?

BACKGROUND: General anesthesia (GA) is often needed for radiotherapy (RT) in young children. This study aimed to evaluate the place of the rituals and/or hypnosis in pediatric in a reference center in pediatric radiation oncology in Rhône-Alpes Auvergne. METHODS: This observational study retrospectively collected data on AG in children<5 years treated by RT in Leon-Berard regional center, Lyon, France between 2003 and 2014. Two-time periods, before and after 2008 have been compared, the second one introducing accompaniment methods such as hypnosis systematically. Explanatory analyses of AG were performed using logistic regression. RESULTS: One hundred and thirty-two children benefited from RT in that period and were included (70 patients until 2008, 62 after 2008). Fifty-three percent were irradiated under GA. There was significant reduction (P<0.1) in the use of GA after 2008. The use of GA was not significantly associated with the RT techniques. The patients more likely to undergo RT without GA were the oldest and the patients treated for abdominal lesions (P<0.01). DISCUSSION: The study confirms that rituals and hypnosis can be used instead of GA in about half of patients under 5 years, even also with high-technicity RT requiring optimal immobilization.

Could time of whole brain radiotherapy delivery impact overall survival in patients with multiple brain metastases?

OBJECTIVE: Whole brain radiotherapy (WBRT) is commonly used to treat brain metastases. Previous studies have explored how radiotherapy treatment time can affect response. The present study evaluated the influence of treatment time on overall survival (OS) for cancer patients receiving WBRT. METHODS: Patients who received WBRT from 2004 to 2016 were included. Demographic information including age, performance status, primary site, dose, fraction, treatment time, and date of death were collected. Based on different percentages of treatment times falling into one time frame (i.e., 100%, ≥80%, ≥70%, or ≥60%), patients were allocated to three cohorts (8:00-11:00 AM, 11:01 AM-2:00 PM, 2:01-5:00 PM). Demographics were compared among cohorts using the Kruskal-Wallis nonparametric test and Fisher exact test. To control the multiple comparisons on select demographic variables a Bonferroni adjusted P value was considered statistically significant. Kaplan-Meier curves were created for OS. Univariate and multivariate Cox proportional hazard (PH) model were used to find predictive factors of OS in all patients, females and males. RESULTS: A total of 755 patients were included with a median age of 66 years. The actuarial median OS was 2.37 months. Treatment time was not associated with OS for all patients or males only. In elderly female patients (>65 years), a significant difference in OS was found among treatment cohorts (P=0.02). Treatment time (when ≥80% or ≥70% of treatment times were in one time frame), age, and Karnofsky performance status (KPS) were significant predictive factors of OS in univariate analysis for females. Only age and KPS remained significant in multivariate analysis. CONCLUSIONS: Time of WBRT delivery for brain metastases was significantly related to OS upon univariate analyses in females only. Future investigations should be conducted prospectively with homogenous patient groups to elucidate the effect of chronotherapy in palliative brain metastases patients as time of WBRT administration may affect OS in specific subsets of patients.

Play-based procedural preparation and support intervention for cranial radiation.

PURPOSE: The primary objective of this study was to examine the relationship between play-based procedural preparation and support intervention and use of sedation in children with central nervous system (CNS) tumors during radiation therapy. The secondary objective was to analyze the cost-effectiveness of the intervention compared to costs associated with daily sedation. METHODS: A retrospective chart review was conducted, and 116 children aged 5-12 years met criteria for inclusion. Outcome measures included the total number of radiation treatments received, the number of treatments received with and without sedation, and the type and duration of interventions, which consisted of developmentally appropriate play, education, preparation, and distraction provided by a certified child life specialist. RESULTS: The results of univariate analyses showed that age, tumor location, and total number and duration of interventions were significantly associated with sedation use during radiation therapy. Multivariate analyses showed that, after adjustment for age, tumor location, and craniospinal radiation, a significant relationship was found between the total number and duration of the interventions and sedation use. The implementation of a play-based procedural preparation and support intervention provided by a certified child life specialist significantly reduced health-care costs by decreasing the necessity of daily sedation. CONCLUSIONS: Support interventions provided by child life specialists significantly decreased both sedation use and the cost associated with daily sedation during cranial radiation therapy in children with CNS tumors. This study supports the value of the child life professional as a play-based developmental specialist and a crucial component of cost-effective healthcare.

Efficacy of therapeutic play for pediatric brain tumor patients during external beam radiotherapy.

OBJECTIVE: External beam radiotherapy (EBRT) is frequently used to improve disease control for pediatric brain tumor patients. However, to facilitate the radiotherapy (RT) procedure, "forced" type interventions including conscious sedation or general anesthesia are frequently used to manage patients' fear and anxiety. The aim of this study was to investigate the effects of therapeutic play (TP) in reducing anxiety for pediatric brain tumor patients treated by EBRT. METHODS: Between April 1st and September 30th, 2009, 19 young brain tumor patients, aged 3-15 years and recommended for RT, were recruited: ten to a control group and nine to the study intervention group. The study group was introduced with TP during EBRT. The Beck Youth Anxiety Inventory and the Faces Anxiety Scale were used to evaluate patients' psychological levels of anxiety. The heart rate variability and salivary cortisol concentrations were used to indicate the patients' physical levels of anxiety. Both the psychological and physiological tests were administered to all subjects before and after the RT procedure. RESULTS: The study group had significantly lower anxiety scores and expressed fewer negative emotions than did the control group before EBRT. CONCLUSIONS: TP can not only improve the quality of medical services but can also reduce costs and staffing demands. In addition, it can help lower young patients' anxiety and fear during medical procedures. As a result, it further decreases the potential negative impacts of hospitalization on these young patients.

Disease control and ototoxicity using intensity-modulated radiation therapy tumor-bed boost for medulloblastoma.

PURPOSE: We previously reported excellent local control for treating medulloblastoma with a limited boost to the tumor bed. In order to decrease ototoxicity, we subsequently implemented a tumor-bed boost using intensity-modulated radiation therapy (IMRT), the clinical results of which we report here. PATIENTS AND METHODS: A total of 33 patients with newly diagnosed medulloblastoma, 25 with standard risk, and 8 with high risk, were treated on an IMRT tumor-bed boost following craniospinal irradiation (CSI). Six standard-risk patients were treated with an institutional protocol with 18 Gy CSI in conjunction with intrathecal iodine-131-labeled monoclonal antibody. The majority of patients received concurrent vincristine and standard adjuvant chemotherapy. Pure-tone audiograms were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. RESULTS: Median age was 9 years old (range, 4-46 years old). Median follow-up was 63 months. Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS) rates for standard-risk patients who received 23.4 or 36 Gy CSI (not including those who received 18 Gy CSI with radioimmunotherapy) were 81.4% and 88.4%, respectively, at 5 years; 5-year PFS and OS rates for high-risk patients were both 87.5%. There were no isolated posterior fossa failures outside of the boost volume. Posttreatment audiograms were available for 31 patients, of whom 6%, at a median follow-up of 19 months, had developed Grade 3 hearing loss. CONCLUSION: An IMRT tumor-bed boost results in excellent local control while delivering a low mean dose to the cochlea, resulting in a low rate of ototoxicity.

Prognostic impact of postoperative, pre-irradiation (18)F-fluoroethyl-l-tyrosine uptake in glioblastoma patients treated with radiochemotherapy.

BACKGROUND AND PURPOSE: Resection is considered as essential for the efficacy of modern adjuvant treatment of glioblastoma multiforme (GBM). Previous studies have indicated that amino acid PET is more specific than contrast enhancement on MRI for detecting residual tumor tissue after surgery. In a prospective study we investigated the prognostic impact of postoperative tumor volume and tumor/brain ratios (TBR) in PET using O-(2-[(18)F]fluoroethyl)-l-tyrosine (FET) in comparison with MRI. MATERIALS AND METHODS: Forty-four patients with GBM were investigated by FET PET and MRI after surgery. Tumor volume in FET PET with a tumor/brain ratio (TBR)>1.6 and a TBR>2, mean and maximum TBR and gadolinium contrast-enhancement on MRI (Gd-volume) were determined. Thereafter patients received a fractionated radiotherapy with concomitant temozolomide (RCX). The median follow-up was 15.4 (3-35) months. The prognostic value of postoperative residual tumor volume in FET PET, TBR(mean,) TBR(max) and Gd-volume was evaluated using Kaplan-Maier estimates for disease-free survival (DFS) and overall survival (OS). RESULTS: Postoperative tumor volume in FET PET had a significant independent influence on OS and DFS (OS 20.0 vs. 6.9 months; DFS 9.6 vs. 5.1 months, p<0.001; cut-off 25 ml). Similar results were observed when a TBR ≥ 2 (cut-off 10 ml) was used to define the tumor volume in (18)F-FET PET. The TBR(mean) and TBR(max) of FET uptake had a significant influence on DFS (p<0.05). Gd-volume in MRI had significant effect on OS and DFS in the univariate analysis. No independent significant influence in OS or DFS could be observed for Gd-volume in MRI. CONCLUSIONS: Our data indicate that the tumor volume in FET PET after surgery of GBM has a strong prognostic impact for these patients. FET PET appears to be helpful to determine the residual tumor volume after surgery of GBM and may serve as a valuable tool for optimal planning of radiation treatment.

Noninvasive focused monitoring and irradiation of head tissue phantoms at microwave frequencies.

In this study, new aspects of our research regarding a novel hybrid system able to provide focused microwave radiometric temperature and/or conductivity measurements and hyperthermia treatment via microwave irradiation are presented. On one hand, it is examined whether the system is capable of sensing real-time progressive local variations of temperature and/or conductivity in customized phantom setups; on the other hand, the focusing attributes of the system are explored for different positions and types of phantoms used for hyperthermia in conjunction with dielectric matching layers surrounding the areas of interest. The main module of the system is an ellipsoidal cavity, which provides the appropriate focusing of the electromagnetic energy on the area of interest. The system has been used for the past few years in experiments with different configuration setups including phantom, animal, and human volunteer measurements yielding promising outcome. The present results show that the system is able to detect local concentrated gradual temperature and conductivity variations expressed as an increase of the output radiometric voltage. Moreover, when contactless focused hyperthermia is performed, the results show significant temperature increase at specific phantom areas. In this case, the effect of the dielectric matching layers placed around the phantoms is critical, thus resulting in the enhancement of the energy penetration depth.

Radiotherapeutic alternatives for previously irradiated recurrent gliomas.

Re-irradiation for recurrent gliomas has been discussed controversially in the past. This was mainly due to only marginal palliation while being associated with a high risk for side effects using conventional radiotherapy. With modern high-precision radiotherapy re-irradiation has become a more wide-spread, effective and well-tolerated treatment option. Besides external beam radiotherapy, a number of invasive and/or intraoperative radiation techniques have been evaluated in patients with recurrent gliomas. The present article is a review on the available methods in radiation oncology and summarizes results with respect to outcome and side effects in comparison to clinical results after neurosurgical resection or different chemotherapeutic approaches.

[Clinical analysis of 67 patients with brain metastases from breast cancer].

BACKGROUND & OBJECTIVE: The incidence of brain metastases from breast cancer seems to be increasing with the improvement of systemic control and survival prolongation. This study was to analyze the clinical characteristics, treatment modalities, and prognostic factors of brain metastases from breast cancer. METHODS: The time from primary diagnosis of breast cancer to brain metastases of 67 breast cancer patients were 0-15 years, and the median time was 2.5 years. Of the 67 patients, 3 received surgery plus radiotherapy, 30 received radiotherapy alone, 3 received chemotherapy alone, 26 received radiochemotherapy, and 5 received no treatment. Kaplan-Meier analysis and log-rank test were used to analyze survival status. RESULTS: Headache was the most common symptom of brain metastases from breast cancer. The median survival time was 4 years. After brain metastases, the median survival time was 11 months. Menstrual status, number of brain metastases, systemic metastases, and different treatment modalities had no correlations to survival time of the patients. CONCLUSIONS: The prognosis of brain metastases from breast cancer is still poor. Radiotherapy remains the standard treatment of brain metastases. The function of chemotherapy needs further study.

The treatment of limited small cell lung cancer: a report of the progress made and future prospects.

The improvements in the treatment of small cell lung cancer over the last 30 years have been realised by understanding that it is a systemic disease, but that areas of bulk and sanctuary require a complementary therapy. Despite successful strategies using combinations and thoracic radiotherapy, there remains uncertainty about what the best regimens are, their timing and their intensity. However, earlier concurrent therapy and rather brief intense chemotherapy and radiotherapy seem to produce the best results in moderately fit patients of all ages. How to select the fit patients and what to do about the less fit ones remains controversial and have economic consequences for governments and payers. Despite a meta-analysis demonstrating the success of prophylactic cranial irradiation (PCI), doubts linger about its safety, despite nothing more than anecdotal evidence from a previous era. The role of surgery continues to be explored, more in Europe than North America or Asia. Strategies for treatment of minimum residual disease seem a focus. New drugs, molecular targeted therapy, immunotherapy and other molecular therapies offer promise and theory, but there is little evidence about their place in the treatment protocols of today.

New three-dimensional moving field radiation therapy for brain tumors.

A new modified rotation radiation method called "three-dimensional moving field radiation therapy" is described. The new method uses rotation in many planes while maintaining the the same isocenter to achieve a good spatial dose distribution. This delivers a high dose to tumors and spares the surrounding normal structures. This easy method can be carried out using the equipment for conventional rotation radiation therapy. The new method was superior to the one plane rotation radiation therapy using a physical phantom with film, a chemical phantom using the iodine-starch reaction, and a new biological model using tumor cells. Treatment of six brain tumors irradiated with total air doses of 50-60 Gy caused no hair loss or radiation necrosis.