Cognitive Decline Secondary to Therapeutic Brain Radiation-Similarities and Differences to Traumatic Brain Injury.

Traumatic brain injury (TBI) resulting from forceful impacts on the torso and head has been of major interest because of the prevalence of such injuries in military personnel, contact sports and the elderly. Cognitive and behavioral changes associated with TBI are also seen following whole brain radiation treatment for cancer and chemotherapy for disseminated tumors. The biological mechanisms involved in the initiation of TBI from impact, radiation, and chemotherapy to loss of cognitive function have several shared characteristics including increases in blood brain barrier permeability, blood vessel density, increases in inflammatory and autoimmune responses, alterations in NMDA and glutamate receptor levels and release of proteins normally sequestered in the brain into the blood and spinal fluid. The development of therapeutic agents that mitigate the loss of cognition and development of behavioral disorders in patients experiencing radiation-induced injury may provide benefit to those with TBI when similar processes are involved on a cellular or molecular level. Increased collaborative efforts between the radiation oncology and the neurology and psychiatry communities may be of major benefit for the management of brain injury from varied environmental insults.

Predicted risks of second malignant neoplasm incidence and mortality due to secondary neutrons in a girl and boy receiving proton craniospinal irradiation.

The purpose of this study was to compare the predicted risks of second malignant neoplasm (SMN) incidence and mortality from secondary neutrons for a 9-year-old girl and a 10-year-old boy who received proton craniospinal irradiation (CSI). SMN incidence and mortality from neutrons were predicted from equivalent doses to radiosensitive organs for cranial, spinal and intracranial boost fields. Therapeutic proton absorbed dose and equivalent dose from neutrons were calculated using Monte Carlo simulations. Risks of SMN incidence and mortality in most organs and tissues were predicted by applying risks models from the National Research Council of the National Academies to the equivalent dose from neutrons; for non-melanoma skin cancer, risk models from the International Commission on Radiological Protection were applied. The lifetime absolute risks of SMN incidence due to neutrons were 14.8% and 8.5%, for the girl and boy, respectively. The risks of a fatal SMN were 5.3% and 3.4% for the girl and boy, respectively. The girl had a greater risk for any SMN except colon and liver cancers, indicating that the girl's higher risks were not attributable solely to greater susceptibility to breast cancer. Lung cancer predominated the risk of SMN mortality for both patients. This study suggests that the risks of SMN incidence and mortality from neutrons may be greater for girls than for boys treated with proton CSI.

Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial.

BACKGROUND: It is unclear whether the benefit of adding whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) for the control of brain-tumours outweighs the potential neurocognitive risks. We proposed that the learning and memory functions of patients who undergo SRS plus WBRT are worse than those of patients who undergo SRS alone. We did a randomised controlled trial to test our prediction. METHODS: Patients with one to three newly diagnosed brain metastases were randomly assigned using a standard permutated block algorithm with random block sizes to SRS plus WBRT or SRS alone from Jan 2, 2001, to Sept 14, 2007. Patients were stratified by recursive partitioning analysis class, number of brain metastases, and radioresistant histology. The randomisation sequence was masked until assignation, at which point both clinicians and patients were made aware of the treatment allocation. The primary endpoint was neurocognitive function: objectively measured as a significant deterioration (5-point drop compared with baseline) in Hopkins Verbal Learning Test-Revised (HVLT-R) total recall at 4 months. An independent data monitoring committee monitored the trial using Bayesian statistical methods. Analysis was by intention-to-treat. This trial is registered at www.ClinicalTrials.gov, number NCT00548756. FINDINGS: After 58 patients were recruited (n=30 in the SRS alone group, n=28 in the SRS plus WBRT group), the trial was stopped by the data monitoring committee according to early stopping rules on the basis that there was a high probability (96%) that patients randomly assigned to receive SRS plus WBRT were significantly more likely to show a decline in learning and memory function (mean posterior probability of decline 52%) at 4 months than patients assigned to receive SRS alone (mean posterior probability of decline 24%). At 4 months there were four deaths (13%) in the group that received SRS alone, and eight deaths (29%) in the group that received SRS plus WBRT. 73% of patients in the SRS plus WBRT group were free from CNS recurrence at 1 year, compared with 27% of patients who received SRS alone (p=0.0003). In the SRS plus WBRT group, one case of grade 3 toxicity (seizures, motor neuropathy, depressed level of consciousness) was attributed to radiation treatment. In the group that received SRS, one case of grade 3 toxicity (aphasia) was attributed to radiation treatment. Two cases of grade 4 toxicity in the group that received SRS alone were diagnosed as radiation necrosis. INTERPRETATION: Patients treated with SRS plus WBRT were at a greater risk of a significant decline in learning and memory function by 4 months compared with the group that received SRS alone. Initial treatment with a combination of SRS and close clinical monitoring is recommended as the preferred treatment strategy to better preserve learning and memory in patients with newly diagnosed brain metastases.

Optimal treatment planning for skull base chordoma: photons, protons, or a combination of both?

PURPOSE: We compared dosimetry of proton (PR), intensity modulated radiation therapy (IMRT) photon (PH), and combined PR and IMRT PH (PP) irradiation of skull base chordomas to determine the most optimal technique. METHODS AND MATERIALS: Computed tomography simulation scans of 5 patients with skull base chordoma were used to generate four treatment plans: an IMRT PH plan with 1-mm planning target volume (PTV; PH1) for stereotactic treatment, an IMRT PH plan with 3-mm PTV (PH3) for routine treatment, a PR plan with beam-specific expansion margins on the clinical target volume, and a PP plan combining PR and PH treatment. All plans were prescribed 74 Gy/Cobalt Gray equivalents (CGE) to the PTV. To facilitate comparison, the primary objective of all plans was 95% or greater PTV prescribed dose coverage. Plans then were optimized to limit dose to normal tissues. RESULTS: PTVs ranged from 4.4 to 36.7 cc in size (mean, 21.6 cc). Mean % PTV receiving 74 Gy was highest in the PP plans (98.4%; range, 96.5-99.2%) and lowest in the PH3 plans (96.1%; range, 95.1-96.7%). PR plans were the least homogeneous and conformal. PH3 plans had the highest mean % volume (V) of brain, brainstem, chiasm, and temporal lobes greater than tolerance doses. The PH1 plans had the lowest brainstem mean % V receiving 67 Gy (V(67Gy); 2.3 Gy; range, 0-7.8 Gy) and temporal lobe mean % V(65Gy) (4.3 Gy; range, 0.1-7.7 Gy). Global evaluation of the plans based on objective parameters revealed that PH1 and PP plans were more optimal than either single-modality PR or PH3 plans. CONCLUSIONS: There are dosimetric advantages to using either PH1 or PP plans, with the latter yielding the best target coverage and conformality.

The risk of developing a second cancer after receiving craniospinal proton irradiation.

The purpose of this work was to compare the risk of developing a second cancer after craniospinal irradiation using photon versus proton radiotherapy by means of simulation studies designed to account for the effects of neutron exposures. Craniospinal irradiation of a male phantom was calculated for passively-scattered and scanned-beam proton treatment units. Organ doses were estimated from treatment plans; for the proton treatments, the amount of stray radiation was calculated separately using the Monte Carlo method. The organ doses were converted to risk of cancer incidence using a standard formalism developed for radiation protection purposes. The total lifetime risk of second cancer due exclusively to stray radiation was 1.5% for the passively scattered treatment versus 0.8% for the scanned proton beam treatment. Taking into account the therapeutic and stray radiation fields, the risk of second cancer from intensity-modulated radiation therapy and conventional radiotherapy photon treatments were 7 and 12 times higher than the risk associated with scanned-beam proton therapy, respectively, and 6 and 11 times higher than with passively scattered proton therapy, respectively. Simulations revealed that both passively scattered and scanned-beam proton therapies confer significantly lower risks of second cancers than 6 MV conventional and intensity-modulated photon therapies.

Stray radiation dose and second cancer risk for a pediatric patient receiving craniospinal irradiation with proton beams.

Proton beam radiotherapy unavoidably exposes healthy tissue to stray radiation emanating from the treatment unit and secondary radiation produced within the patient. These exposures provide no known benefit and may increase a patient's risk of developing a radiogenic cancer. The aims of this study were to calculate doses to major organs and tissues and to estimate second cancer risk from stray radiation following craniospinal irradiation (CSI) with proton therapy. This was accomplished using detailed Monte Carlo simulations of a passive-scattering proton treatment unit and a voxelized phantom to represent the patient. Equivalent doses, effective dose and corresponding risk for developing a fatal second cancer were calculated for a 10-year-old boy who received proton therapy. The proton treatment comprised CSI at 30.6 Gy plus a boost of 23.4 Gy to the clinical target volume. The predicted effective dose from stray radiation was 418 mSv, of which 344 mSv was from neutrons originating outside the patient; the remaining 74 mSv was caused by neutrons originating within the patient. This effective dose corresponds to an attributable lifetime risk of a fatal second cancer of 3.4%. The equivalent doses that predominated the effective dose from stray radiation were in the lungs, stomach and colon. These results establish a baseline estimate of the stray radiation dose and corresponding risk for a pediatric patient undergoing proton CSI and support the suitability of passively-scattered proton beams for the treatment of central nervous system tumors in pediatric patients.

Contemporary Proton Therapy Systems Adequately Protect Patients from Exposure to Stray Radiation.

Proton beam therapy has provided safe and effective treatments for a variety of adult cancers. In recent years, there has been increasing interest in utilizing proton therapy for pediatric cancers because it allows better sparing of healthy tissues. Minimizing exposures of normal tissues is especially important in children because they are highly susceptible to consequential late effects, including the development of a radiogenic second cancer, which may occur years or even decades after treatment of the first cancer. While the dosimetric advantage of therapeutic proton beams is well understood, relatively little attention has been paid to the whole-body exposure to stray neutron radiation that is inherent in proton therapy. In this report, we review the physical processes that lead to neutron exposures, discuss the potential for mitigating these exposures using advanced proton beam delivery systems, and present a comparative analysis of predicted second cancer incidence following various external beam therapies. In addition, we discuss uncertainties in the relative biological effectiveness of neutrons for carcinogenesis and the impact that these uncertainties have on second-cancer risk predictions for survivors of adult and childhood cancer who receive proton therapy.

Polymorphisms in the interleukin-4 receptor gene are associated with better survival in patients with glioblastoma.

PURPOSE: Previous literature provides some evidence that atopic diseases, IgE levels, and inflammatory gene polymorphisms may be associated with risk of glioblastoma. The purpose of this study was to investigate the effects of certain inflammatory gene single nucleotide polymorphisms (SNP) on patient survival. Malignant gliomas are the most common type of primary brain tumor in adults, however, few prognostic factors have been identified. EXPERIMENTAL DESIGN: Using 694 incident adult glioma cases identified between 2001 and 2006 in Harris County, TX, we examined seven SNPs in the interleukin (IL)-4, IL-13, and IL-4 receptor (IL4R) genes. Cox proportional hazards regression was used to examine the association between the SNPs and overall and long-term survival, controlling for age at diagnosis, time between diagnosis and registration, extent of surgical resection, radiation therapy, and chemotherapy. RESULTS: We found that among high-grade glioma cases, IL4R rs1805016 (TT versus GT/GG) was significantly protective against mortality over time [hazard ratios (HR), 0.59; 95% confidence intervals (CI), 0.40-0.88]. The IL4R rs1805016 and rs1805015 TT genotypes were both found to be significantly associated with survival beyond 1 year among patients with high-grade glioma (HR, 0.44; 95% CI, 0.27-0.73 and HR, 0.63; 95% CI, 0.44-0.91, respectively). Furthermore, the IL4R haplotype analysis showed that SNPs in the IL4R gene may be interacting to affect long-term survival among high-grade glioma cases. CONCLUSIONS: These findings indicate that polymorphisms in inflammation pathway genes may play an important role in glioma survival. Further research on the effects of these polymorphisms on glioma prognosis is warranted.

Multimodality treatment of osteosarcoma: radiation in a high-risk cohort.

PURPOSE: Chemotherapy during radiation and/or bone-seeking radioisotope therapy (153-samarium; 1 mCi/kg) during radiation may improve osteosarcoma cancer control. PATIENTS AND METHODS: We analyzed our preliminary radiation experience in high-risk, metastatic, and/or recurrent patients during a consecutive period of 20 months (May 2005-December 2006). RESULTS: Thirty-nine high-risk osteosarcoma patients had radiotherapy; 119 sites were irradiated. A median four sites were irradiated per patient (range 1-14). The median radiation dose and number of fractions of radiation was 30 Gy in 10 fractions (range 10-70 Gy in 4-35 fractions). Chemotherapy, most commonly ifosfamide or methotrexate, was used in 80% (100/119) radiotherapy courses. Of 38 painful sites, 29 had improvement (76%), 4 had no change (10%), and 5 had more pain (13%). Objective and potentially durable responses were documented using PET-CT and bone scans with persistent and sustained reduction of standard uptake values (SUVs; initial SUV of indication lesion 9.5 became <4 at all subsequent time points) and serial bone scans [improvement in 29/39 (72%); stable 10/39 (25%), worse 1/39 (3%)]. The actuarial 4-year survival from development of metastasis was 39%. CONCLUSIONS: Our early results suggest that the use of multimodality therapy including chemotherapy with radiation in unresectable osteosarcoma may be beneficial.

Fludarabine allows dose reduction for total body irradiation in pediatric hematopoietic stem cell transplantation.

PURPOSE: To examine, in the setting of total body irradiation (TBI) for the preparation of pediatric hematopoietic stem cell transplantation (HSCT), whether TBI dose can be reduced without compromising the efficacy of a regimen consisting of fludarabine and radiotherapy; and whether there is any increased risk of pulmonary toxicity due to the radiosensitizing effect of fludarabine. METHODS AND MATERIALS: A total of 52 pediatric patients with hematologic malignancies received TBI-based conditioning regimens in preparation for allogeneic HSCT. Twenty-three patients received 12 Gy in 4 daily fractions in combination with cyclophosphamide, either alone or with other chemotherapeutic and biologic agents. Twenty-nine patients received 9 Gy in 3 fractions in conjunction with fludarabine and melphalan. Clinical and radiation records were reviewed to determine engraftment, pulmonary toxicity (according to Radiation Therapy Oncology Group criteria), transplant-related mortality, recurrence of primary disease, and overall survival. RESULTS: The two groups of patients had comparable pretransplant clinical characteristics. For the 12-Gy and 9-Gy regimens, the engraftment (89% and 93%; p = 0.82), freedom from life-threatening pulmonary events (65% and 79%; p = 0.33), freedom from relapse (60% and 73%; p = 0.24), and overall survival (26% and 47%; p = 0.09) were not statistically different. CONCLUSIONS: The addition of fludarabine and melphalan seems to allow the dose of TBI to be lowered to 9 Gy without loss of engraftment or antitumor efficacy.

Gastrostomy in oropharyngeal cancer patients with ERCC4 (XPF) germline variants.

PURPOSE: ERCC4 (XPF) plays a role in both recombinant DNA repair and nucleotide excision repair, which involve repairing radiation-induced genetic damage. We hypothesized that two ERCC4 single-nucleotide polymorphisms are associated with normal-tissue toxicity in patients treated with radiotherapy for oropharyngeal squamous cell carcinoma (OPSCC). METHODS AND MATERIALS: A retrospective review of the medical records of 130 patients with OPSCC who were prospectively recruited into a molecular epidemiologic study was performed to determine whether a long-term percutaneous feeding gastrostomy (LPFG) tube (a tube required for more than 180 days) had been used during and after definitive radiotherapy. We determined the genotype of the ERCC4 G1244A and T2505C polymorphisms using standard polymerase chain reaction-restriction fragment-length polymorphism techniques on DNA extracted from peripheral blood lymphocytes. RESULTS: Of 130 patients, 100 (77%) were evaluable for the ERCC4 G1244A polymorphism in exon 8, and 122 (94%) were evaluable for the ERCC4 T2505C polymorphism in exon 11. The ERCC4 G1244A polymorphism was associated with a decreased need for LPFG, but this was not statistically significant (adjusted odds ratio = 0.53; 95% confidence interval, 0.10-2.78). Sixteen (32%), 9 (14%), and 1 (10%) of patients with the wild-type homozygous TT genotype of ERCC4 T2505C, the heterozygous TC genotype, and the homozygous CC polymorphic genotype, respectively, required LPFG. These results suggest that the ERCC4 2505C allele was associated with a reduced need for LPFG (adjusted odds ratio = 0.20; 95% confidence interval, 0.06-0.67). Furthermore, the need for LPFG was reduced by having more than 1 ERCC4 2505C allele and further for having both the ERCC4 1244A and 2505C polymorphic alleles, but this was not statistically significant. In addition, the actual time of gastrostomy dependence was associated with the T2505C polymorphism based on the Kaplan-Meier method (p = 0.03). CONCLUSIONS: Our findings suggest that the ERCC4 T2505C polymorphism may be associated with improved recovery from radiation treatment toxicity in patients with OPSCC. Further study with larger sample sizes and prospective measure of radiotherapy-induced toxicity is warranted.