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.

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.

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.