RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin.

Anthracyclines, such as doxorubicin, are highly effective chemotherapeutic agents, yet are associated with increased risk of cardiotoxicity. The genes and pathways involved in the development of heart damage following doxorubicin exposure in humans remain elusive. Our objective was to explore time- and dose-dependent changes in gene expression via RNA sequence (RNAseq) that mediate doxorubicin response in human iPSC-cardiomyocytes following 50, 150, or 450 nM exposure for 2, 7, or 12 days. Clustering and differential expression analyses were conducted to identify genes with altered expression. Samples clustered in dose and time-dependent manners, and MCM5, PRC1, NUSAP1, CENPF, CCNB1, MELK, AURKB, and RACGAP1 were consistently significantly differentially expressed between untreated and treated conditions. These genes were also significantly downregulated in pairwise analyses, which was validated by reverse transcription polymerase chain reaction (RT-PCR). Pathway analysis identified the top canonical pathways involved in response, implicating DNA damage repair response and the cell cycle as having roles in the development of doxorubicin-induced cardiotoxicity in the human cardiomyocyte.

Nonrandomized comparison of neurofibromatosis type 1 and non-neurofibromatosis type 1 children who received carboplatin and vincristine for progressive low-grade glioma: A report from the Children's Oncology Group.

BACKGROUND: To evaluate tumor responses, event-free survival (EFS), overall survival (OS), and toxicity of chemotherapy, children with neurofibromatosis type 1 (NF1) and progressive low-grade glioma were enrolled into the Children's Oncology Group (COG) A9952 protocol and treated with carboplatin and vincristine (CV). METHODS: Non-NF1 patients were randomized to CV or thioguanine, procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, and vincristine in COG A9952. NF1 patients were assigned to CV only. NF1 patients and non-NF1 patients who were treated with CV were compared with respect to baseline characteristics, toxicity, tumor responses, EFS, and OS. RESULTS: A total of 127 eligible patients with NF1 were nonrandomly assigned to CV: 42 NF1 patients (33%) had events, and 6 (4.7%) died. The 5-year EFS rate was 69% ± 4% for the CV-NF1 group and 39% ± 4% for the CV-non-NF1 group (P < .001). In a univariate analysis, NF1 children had a significantly higher tumor response rate and superior EFS and OS in comparison with CV-treated children without NF1. NF1 patients and non-NF1 patients differed significantly in amount of residual tumor, extent of resection, tumor location, and pathology. According to a multivariate analysis, NF1 was independently associated with better EFS (P < .001) but not with OS. NF1 patients also had a decreased risk of grade 3 or 4 toxicities in comparison with non-NF1 patients. Three second malignant neoplasms occurred in NF1 patients receiving CV (CV-NF1 group) at a median of 7.8 years (range, 7.3-9.4 years) after enrollment, but there were none in the non-NF1 group. CONCLUSIONS: Children with NF1 tolerated CV well and had tumor response rates and EFS that were superior to those for children without NF1. Cancer 2016;122:1928-36. © 2016 American Cancer Society.

Fatal juvenile xanthogranuloma presenting as a sellar lesion: case report and literature review.

INTRODUCTION: Juvenile xanthogranuloma (JXG) is a histiocytic condition in the spectrum of non-Langerhans histiocytosis that preferentially affects children. Rarely this condition can involve the central nervous system (CNS) with devastating consequences. METHODS: The authors report the unique case of an 11-year-old child who initially presented with a sellar lesion without evidence of the cutaneous stigmata typical of JXG. She was later discovered to have JXG following initial diagnosis of granulomatous hypophysitis, with development of widespread intracranial disease and subsequent neurological deterioration. She underwent subtotal resection of her sellar lesion followed by whole brain radiation and systemic chemotherapy; however, she succumbed to her disseminated disease within 1 month of the JXG diagnosis. CONCLUSIONS: This is a rare case of fatal disseminated intracranial JXG without cutaneous manifestations. Additionally, the initial presentation as a sellar lesion is particularly unusual and seldom described in the literature.

Treatment of recurrent diffuse intrinsic pontine glioma: the MD Anderson Cancer Center experience.

Recurrent diffuse intrinsic pontine gliomas (DIPG) are traditionally treated with palliative care since no effective treatments have been described for these tumors. Recently, clinical studies have been emerging, and individualized treatment is attempted more frequently. However, an informative way to compare the treatment outcomes has not been established, and historical control data are missing for recurrent disease. We conducted a retrospective chart review of patients with recurrent DIPG treated between 1998 and 2010. Response progression-free survival and possible influencing factors were evaluated. Thirty-one patients were identified who were treated in 61 treatment attempts using 26 treatment elements in 31 different regimens. The most frequently used drugs were etoposide (14), bevacizumab (13), irinotecan (13), nimotuzumab (13), and valproic acid (13). Seven patients had repeat radiation therapy to the primary tumor. Response was recorded after 58 treatment attempts and was comprised of 0 treatment attempts with complete responses, 7 with partial responses, 20 with stable diseases, and 31 with progressive diseases The median progression-free survival after treatment start was 0.16 years (2 months) and was found to be correlated to the prior time to progression but not to the number of previous treatment attempts. Repeat radiation resulted in the highest response rates (4/7), and the longest progression-free survival. These data provide a basis to plan future clinical trials for recurrent DIPG. Repeat radiation therapy should be tested in a prospective clinical study.

Feasibility, reliability, and validity of the Pediatric Quality of Life Inventory ™ generic core scales, cancer module, and multidimensional fatigue scale in long-term adult survivors of pediatric cancer.

BACKGROUND: Most health-related quality of life assessments are designed for either children or adults and have not been evaluated for adolescent and young adult survivors of pediatric cancer. The objective of this study was to examine the feasibility, reliability, and validity of the Pediatric Quality of Life Inventory (PedsQL ™ Generic Core Scales, Cancer Module, and Multidimensional Fatigue Scale in adult survivors of pediatric cancer. METHODS: Adult survivors (n = 64; Mean age 35 year old; >2 years after treatment) completed the PedsQL™ Generic Core Scales, Cancer Module, and Multidimensional Fatigue Scale. Feasibility was examined with floor and ceiling effects; and internal consistency was determined by Cronbach's coefficient alpha calculations. Inter-factor correlations were also assessed. RESULTS: Significant ceiling effects were observed for the scales of social function, nausea, procedural anxiety, treatment anxiety, and communication. Internal consistency for all subscales was within the recommended ranges (α ≥ 0.70). Moderate to strong correlations between most Cancer Module and Generic Core Scales (r = 0.25 to r = 0.76) and between the Multidimensional Fatigue Scale and Generic Core Scales (r = 0.37 to r = 0.73). CONCLUSIONS: The PedsQL™ Generic Core Scales, Cancer Module, and Multidimensional Fatigue Scale appear to be feasible for an older population of pediatric cancer survivors; however, some of the Cancer Module Scales (nausea, procedural/treatment anxiety, and communication) were deemed not relevant for long-term survivors. More information is needed to determine whether the issues addressed by these modules are meaningful to long-term adult survivors of pediatric cancers.

Associations between leisure-time physical activity and health-related quality of life among adolescent and adult survivors of childhood cancers.

OBJECTIVE: Survivors of childhood cancer are at an increased risk for reduced quality of life (QOL), yet few studies have explored factors associated with improving health-related QOL (HRQOL) in this population. We thus explored the relationship between physical activity (PA) and HRQOL among survivors of childhood cancer. METHODS: A total of 215 survivors of childhood lymphoma, leukemia, and central nervous system cancers completed mailed surveys that elicited information regarding leisure-time PA (LTPA) measured in metabolic equivalents, HRQOL, and diagnostic and demographic factors. Correlations and adjusted regression models were used to explore the relationship between LTPA and HRQOL. RESULTS: In the total sample, modest, yet significant linear associations were observed between LTPA and overall HRQOL (beta=0.17, p<0.01), as well as each of the respective subscales (beta=0.11-0.23 and p's<0.05 to <0.001). Among adolescent survivors of childhood cancer, LTPA was significantly associated with overall HRQOL (beta=0.27), cancer worry (beta=0.36), cognitive function (beta=0.32), body appearance (beta=0.29), and social function (beta=0.27) (all p's<0.05). Among adult survivors of childhood cancer, LTPA was only significantly associated with physical function (beta=0.28, p<0.001). CONCLUSIONS: Significant associations exist between LTPA and HRQOL; however, the association was stronger and observed in more domains for adolescent survivors of childhood cancer. More research is needed to determine the antecedents and consequences of PA in this population.

Magnetic resonance imaging features of pilocytic astrocytoma of the brain mimicking high-grade gliomas.

OBJECTIVE: The typical magnetic resonance/computed tomographic imaging appearance of pilocytic astrocytoma (PA) is that of a cyst with an intensely enhancing mural nodule. The purpose of this study was to illustrate the aggressive imaging features of PA. METHODS: One hundred patients referred to the cancer center with brain tumors histologically proven to be PA were retrospectively reviewed (95 by magnetic resonance imaging and 5 by computed tomographic imaging) and analyzed. RESULTS: The patient population includes 76 pediatric patients younger than 18 years and 24 adults ranging from 19 to 45 years old. Tumor locations consisted of the following: optic chiasm (22), lateral ventricle (3), thalamus (12), basal ganglia (1), cerebral hemisphere (10), corpus callosum (2), brain stem (26), fourth ventricle (1), and cerebellum (23). The imaging appearance of PA consisted of typical features in 71 cases and aggressive features in 29 cases. CONCLUSIONS: It is important to recognize the aggressive imaging appearance of PA (grade 1 astrocytoma) because it can be mistaken for high-grade gliomas and may thus lead to inappropriate therapy. Despite the aggressive imaging appearance of PA, there is no histopathologic evidence of anaplasia.

Influence of valproic acid on outcome of high-grade gliomas in children.

BACKGROUND: Chemotherapy has limited effects in the treatment of high-grade gliomas (HGGs). Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, may sensitize HGGs to radiochemotherapy. As the drug has been given frequently as an antiepileptic drug, a retrospective analysis was conducted to ensure relevant information was not missed before a prospective study was launched. MATERIALS AND METHODS: An analysis of 66 pediatric patients (range, 1-19 years of age) with glioblastoma multiforme (GBM) (n=40) or anaplastic astrocytoma (AA) (n=26) was retrospectively conducted for predictors of survival and response and for effects of VPA on outcome or toxicity. RESULTS: The overall survival (OS) was better for AA (p=0.0114) and complete resection (p<0.00005) and event-free survival (EFS) was better for complete resection (p=0.0049). Nine patients received VPA (for seizure) plus further oncological treatment. The most severe adverse effect was a pulmonary embolism (n=1); no other severe side-effects were noted. The response to nonsurgical treatment after 8 weeks was: complete response (CR): 0, partial response (PR): 3, stable disease (SD): 4, progressive disease (PD): 2. Some of the patients with SD responded later resulting in best response: CR:0, PR:5, SD:2, PD:2. CONCLUSION: Treatment with VPA plus radiochemotherapy is well tolerated with an encouraging response rate.

Hypertension Susceptibility Loci are Associated with Anthracycline-related Cardiotoxicity in Long-term Childhood Cancer Survivors.

Anthracycline-based chemotherapy is associated with dose-dependent, irreversible damage to the heart. Childhood cancer survivors with hypertension after anthracycline exposure are at increased risk of cardiotoxicity, leading to the hypothesis that genetic susceptibility loci for hypertension may serve as predictors for development of late cardiotoxicity. Therefore, we determined the association between 12 GWAS-identified hypertension-susceptibility loci and cardiotoxicity in a cohort of long-term childhood cancer survivors (N = 108) who received anthracyclines and were screened for cardiac function via echocardiograms. Hypertension-susceptibility alleles of PLCE1:rs9327264 and ATP2B1:rs17249754 were significantly associated with cardiotoxicity risk conferring a protective effect with a 64% (95% CI: 0.18-0.76, P = 0.0068) and 74% (95% CI: 0.07-0.96, P = 0.040) reduction in risk, respectively. In RNAseq experiments of human induced pluripotent stem cell (iPSC) derived cardiomyocytes treated with doxorubicin, both PLCE1 and ATP2B1 displayed anthracycline-dependent gene expression profiles. In silico functional assessment further supported this relationship - rs9327264 in PLCE1 (P = 0.0080) and ATP2B1 expression (P = 0.0079) were both significantly associated with daunorubicin IC50 values in a panel of lymphoblastoid cell lines. Our findings demonstrate that the hypertension-susceptibility variants in PLCE1 and ATP2B1 confer a protective effect on risk of developing anthracycline-related cardiotoxicity, and functional analyses suggest that these genes are influenced by exposure to anthracyclines.

Racial Differences in 20-Year Cardiovascular Mortality Risk Among Childhood and Young Adult Cancer Survivors.

PURPOSE: Whether cardiovascular disease (CVD) risk differs according to race and cancer type among survivors of childhood or young adulthood cancers is unknown. METHODS: Data from the years 1973-2011 were analyzed using the Surveillance, Epidemiology, and End Results (SEER) registries. Cases were categorized by ICD-0-3/WHO 2008 Adolescent and Young Adult classification. CVD death was determined by ICD-10 codes for diseases of the heart, atherosclerosis, cerebrovascular diseases, or other diseases of the arteries. Cox proportional hazards models were fitted to evaluate the hazard ratio (HR) and 95% confidence intervals (CIs) for the effects of race on time-to-event outcomes. RESULTS: A total of 164,316 cases of childhood and young adult primary cancers were identified. There were 43,335 total and 1466 CVD deaths among Black and White survivors. Black survivors had higher risks of all-cause mortality (HR: 1.75, 95% CI: 1.70-1.7) and CVD mortality (HR: 2.13, 95% CI: 1.85-2.46) compared to White survivors. The increased risk of CVD for Black survivors compared to White survivors persisted at 5-years (HR: 2.38, 95% CI: 1.83-3.10), 10-years (HR: 2.59, 95% CI: 2.09-3.21), and 20-years (HR: 2.31, 95% CI: 1.95-2.74) postdiagnosis, and varied by cancer type, with the highest HRs for melanoma (HR: 8.16, 95% CI: 1.99-33.45) and thyroid cancer (HR: 3.43, 95% CI: 1.75-6.73). CONCLUSIONS: Black survivors of childhood or young adulthood cancers have a higher risk of CVD mortality compared to Whites that varies by cancer type. Knowledge of at-risk populations is important to guide surveillance recommendations and behavioral interventions. Further study is needed to understand the etiology of racial differences in CVD mortality in this population.

Psychometric Analysis of the Three-Factor Eating Questionnaire-R18V2 in Adolescent and Young Adult-Aged Central Nervous System Tumor Survivors.

PURPOSE: Adolescent and young adult (AYA)-aged central nervous system (CNS) tumor survivors are an understudied population that is at risk of developing adverse health outcomes, such as obesity. Long-term follow-up guidelines recommend monitoring those at risk of obesity, thus motivating the need for an eating behavior questionnaire. An abbreviated online version of the Three-Factor Eating Questionnaire (TFEQ-R18v2) has been developed, but its applicability to this population is not yet known. This study investigated the instrument's factor structure and reliability in this population. METHODS: AYA-aged CNS tumor survivors (n = 114) aged 15-39 years completed the TFEQ-R18V2 questionnaire online. Confirmatory factor analysis was used to examine the fit of the three-factor structure (uncontrollable eating, cognitive restraint, and emotional eating [EE]) and reliability (internal consistency of the TFEQ-R18v2). Associations between the three factors and body mass index (BMI) were assessed by linear regression. RESULTS: The theorized three-factor structure was supported in our population (RMSEA = 0.056 and CFI = 0.98) and demonstrated good reliability (α of 0.81-0.93). EE (ß = 0.07, 95% CI 0.02-0.13) was positively associated with BMI, whereas the other two subscale scores were not. CONCLUSION: The TFEQ-R18v2 instrument holds promise for research and clinical use among AYA-aged CNS tumor survivors. The instrument may be a useful tool for researchers to develop tailored weight management strategies. It also may be a valuable tool for clinicians to monitor survivors who are at risk of obesity and to facilitate referral. Our results also suggest that EE in this population should be further investigated as a potential target for intervention.

Triiodothyronine supplementation for hypothalamic obesity.

Patients with suprasellar lesions develop profound hypothalamic obesity and listlessness with no effective treatment. We added triiodothyronine (T(3)) supplementation in 3 such patients and present their response. All had previous nutritional counseling without benefit. All were treated for diabetes insipidus (DI) and hypopituitarism; serum free thyroxine (T(4)) level was normal. A 24-year-old woman (pineal tumor and astrocytoma) had weight gain (4.7 kg/yr for 3 years), cold intolerance, fatigue, dry skin, and constipation; after T(3), she lost 14 kg over 27 months and reported overall improvement. Her bone mineral density also improved. A 10.6-year-old boy (optic glioma) was gaining 6 kg/yr for 4 years; after T(3) supplement, he lost 4.3 kg over 11 months. A 12-year-old girl (mixed germ cell tumor) had weight gain (8.3 kg/yr for 3 years) and listlessness; after T(3), she lost 8.1 kg over 16 months and had improved alertness. All patients were asymptomatic despite supraphysiologic T(3) levels. We suggest that T(3) may serve as a simple and effective supplement, which can promote weight loss and improve the well being of these patients with hypothalamic obesity.

Transsphenoidal removal of intrasellar pilocytic astrocytoma.

A 26-year-old man with a sellar pilocytic astrocytoma had a recurrent non-enhancing mass located in the sellar/suprasellar region visible on MRI. Due to tumor progression and worsening vision, the mass was completely resected through a transsphenoidal approach. Postoperatively, the patient's vision improved and imaging showed complete removal of the tumor and optic pathway decompression. Pilocytic astrocytomas originating in suprasellar structures can intrude into the sella, and should be included in the differential diagnosis of intrasellar tumors. The transsphenoidal approach can be effective for resecting such tumors.

Adult versus Pediatric Neuroblastoma: The M.D. Anderson Cancer Center Experience.

Background. Staging and treatment of adult neuroblastoma has yet to be formalized. We sought to determine the utility of the pediatric classification system in adults and determine the efficacy of different treatment modalities. Methods. Medical records of 118 adults (patients >17 years old) and 112 pediatric patients (ages 2-17), who were treated for neuroblastoma at M.D. Anderson Cancer Center from January 1994 to September 2012, were reviewed. International neuroblastoma risk group (INRG) variables were abstracted. The primary outcome of interest was actuarial progression-free survival. Results. Median age of pediatric patients was 5 years (range 3-16) and 47 years (range 18-82) for adult patients. There were no differences in PFS or OS between stage-matched risk categories between pediatric and adult patients (L1-P = 0.40, L2-P = 0.54, and M-P = 0.73). In the treatment of L1 disease, median PFS for adults treated with surgery and radiation was 11.1 months compared with single modality local treatment ± chemotherapy (6.4 and 5.1 months, resp.; P = 0.07). Median PFS in L2 adult patients was 5.2 months with local therapy and 4 months with the addition of chemotherapy (P = 0.23). Conclusions. Adult and pediatric patients with neuroblastoma achieve similar survival outcomes. INRG classification should be employed to stratify adult neuroblastoma patients and help select treatment.

Health-related quality of life, lifestyle behaviors, and intervention preferences of survivors of childhood cancer.

PURPOSE: Childhood cancer survivors (CCSs) are at increased risk for poor health-related quality of life (HRQOL) and chronic health conditions-both of which can be exacerbated by unhealthy lifestyle behaviors. Developing a clearer understanding of the associations between HRQOL, lifestyle behaviors, and medical and demographic variables (e.g., age/developmental stage at time of diagnosis) is an important step toward developing more targeted behavioral interventions for this population. METHOD: Cross-sectional questionnaires were completed by 170 CCSs who were diagnosed with leukemia, lymphoma, sarcoma, or a cancer of the central nervous system (CNS) and treated at a comprehensive cancer center between 1992 and 2007. Questionnaires addressed weight status, lifestyle behaviors, aspects of HRQOL, and intervention preferences. RESULTS: Adolescent and young adult survivors (AYAs) and survivors of CNS tumors or lymphoma reported significantly (p < .05) poorer HRQOL across multiple domains compared to those diagnosed at an earlier age, survivors of leukemia or sarcoma, and healthy populations. A significant proportion also failed to meet national recommendations for dietary intakes (39-94 %) and physical activity (65 %). Female survivors reported poorer physical functioning and consumed less dietary fiber and fruits and vegetables than did male survivors. They also expressed the strongest interest in participating in diet and exercise interventions. CONCLUSION: Findings support the premise that females, AYAs, and survivors of cancers of the CNS or lymphoma are "at risk" subgroups within the CCS population for poor dietary practices, sedentary behaviors, and poor HRQOL. Future research should focus on developing diet and PA interventions to improve HRQOL that target these groups. IMPLICATIONS FOR CANCER SURVIVORS: Greater consideration of the role of gender, developmental stage, and the HRQOL challenges facing CCSs may help researchers to develop targeted behavioral interventions for those who stand to benefit the most.

Oral extragonadal yolk sac tumor in a patient with Aicardi syndrome: putative origin and differential diagnosis.

We report, for the first time, a primary oral presentation of a germ cell yolk sac tumor in a 4-year-old girl with Aicardi syndrome. The diagnosis, differential diagnosis, and histogenesis are discussed.

Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children's Oncology Group.

PURPOSE Surgery is curative therapy for pediatric low-grade gliomas (LGGs) in areas of the brain amenable to complete resection. However, LGGs located in areas where complete resection is not possible can threaten both function and life. The purpose of this study was to compare two chemotherapy regimens for LGGs in children younger than age 10 years for whom radiotherapy was felt by the practitioner to pose a high risk of neurodevelopmental injury. PATIENTS AND METHODS Previously untreated children younger than age 10 years with progressive or residual LGGs were eligible. Children were randomly assigned to receive carboplatin and vincristine (CV) or thioguanine, procarbazine, lomustine, and vincristine (TPCV). Children with neurofibromatosis are reported separately. Results Of 274 randomly assigned patients who met eligibility requirements, 137 received CV and 137 received TPCV. The 5-year event-free survival (EFS) and overall survival (OS) rates for all eligible patients were 45% ± 3.2% and 86% ± 2.2%, respectively. The 5-year EFS rates were 39% ± 4% for CV and 52% ± 5% for TPCV (stratified log-rank test P = .10; cure model analysis P = .007). On multivariate analysis, factors independently predictive of worse EFS and OS were younger age and tumor size greater than 3 cm(2). Tumor location in the thalamus was also associated with poor OS. CONCLUSION The difference in EFS between the regimens did not reach significance on the basis of the stratified log-rank test. The 5-year EFS was higher for TPCV on the basis of the cure model analysis. Differences in toxicity may influence physician choice of regimens.

Health behaviors and weight status of childhood cancer survivors and their parents: similarities and opportunities for joint interventions.

Childhood cancer survivors are at increased risk for chronic health conditions that may be influenced by their cancer treatment and unhealthy lifestyle behaviors. Despite the possibility that interventions targeting the survivor-parent dyad may hold promise for this population, a clearer understanding of the role of family factors and the lifestyle behaviors of both survivors and parents is needed. A mailed cross-sectional survey was conducted in 2009 to assess weight status (body mass index), lifestyle behaviors (eg, diet, physical activity), and the quality of the parent-child relationship among 170 childhood cancer survivors who were treated at MD Anderson Cancer Center and 114 of their parents (80% mothers). Survivors were more physically active and consumed more fruits and vegetables than their parents. However, fewer than half of survivors or parents met national guidelines for diet and physical activity, and their weight status and fat intakes were moderately correlated (r=.30-.57; P<0.001). Multilevel models showed that, compared with survivors with better than average relationships, those with poorer than average relationships with their parents were significantly more likely to consume high-fat diets (P<0.05). Survivors and their parents may thus benefit from interventions that address common lifestyle behaviors, as well as issues in the family environment that may contribute to an unhealthy lifestyle.

Focal and craniospinal irradiation for patients with intracranial germinoma and patterns of failure.

BACKGROUND: The authors compared the patterns of failure in patients with intracranial germinoma who were managed with either chemotherapy and focal irradiation or with craniospinal irradiation (CSI). METHODS: A retrospective review was conducted on 21 patients with intracranial germinoma and treated with radiotherapy (RT) to the central nervous system at The University of Texas M. D. Anderson Cancer Center from 1981 to 2002. The study group was comprised of 13 males and 8 females with a median age at diagnosis of 19 years. Nine patients received chemotherapy prior to focal RT. Twelve patients received CSI. RESULTS: The actuarial 10-year survival rate for all patients was 86%. The overall survival rate at 10 years was 89% for patients who received focal RT and 83% for patients who received CSI (P = .73). The 10-year local control rate in the brain for patients who received focal irradiation was 59% compared with 100% for patients who received CSI (P = .08). The rate of distant control in the spine at 5 years was 62% for patients who received focal irradiation and 100% for patients who received CSI (P = .04). CONCLUSIONS: Although focal techniques of irradiation with chemotherapy are attractive methods that limited the volume irradiated, the strategy appeared to be associated with increased rates of failures in the brain and spine.