Phase II TPDCV protocol for pediatric low-grade hypothalamic/chiasmatic gliomas: 15-year update.

To report long-term results for children with low-grade hypothalamic/chiasmatic gliomas treated on a phase II chemotherapy protocol. Between 1984 and 1992, 33 children with hypothalamic/chiasmatic LGGs received TPDCV chemotherapy on a phase II prospective trial. Median age was 3.0 years (range 0.3-16.2). Twelve patients (36%) underwent STRs, 14 (42%) biopsy only, and seven (21%) no surgery. Twenty patients (61%) had pathologic JPAs, nine (27%) grade II gliomas, and four (12%) no surgical sampling. Median f/u for surviving patients was 15.2 years (range 5.3-20.7); 20 of the 23 surviving patients had 14 or more years of follow-up. Fifteen-year PFS and OS were 23.4 and 71.2%, respectively. Twenty-five patients progressed, of whom 13 are NED, two are AWD, and 10 have died. All children who died were diagnosed and first treated at age three or younger. Age at diagnosis was significantly associated with relapse and survival (P = 0.004 for PFS and P = 0.037 for OS). No PFS or OS benefit was seen with STR versus biopsy/no sampling (P = 0.58 for PFS, P = 0.59 for OS). For patients with JPAs and WHO grade II tumors, the 15-year PFS was 18.8 and 22.2% (P = 0.95) and 15-year OS was 73.7 and 55.6% (P = 0.17), respectively. Upfront TPDCV for children with hypothalamic/chiasmatic LGGs resulted in 15-year OS of 71.2% and 15-year PFS of 23.4%. No survival benefit is demonstrated for greater extent of resection. Age is a significant prognostic factor for progression and survival.

Changes in symptom clusters in patients undergoing radiation therapy.

GOALS OF WORK: The goals of the study were to determine the occurrence rates for and the severity of symptoms at the middle, end, and 1 month after the completion of radiation therapy (RT), to determine the number and types of symptom clusters at these three time points, and to evaluate for changes over time in these symptom clusters. MATERIALS AND METHODS: Symptom occurrence and severity were evaluated using the Memorial Symptom Assessment Scale (MSAS) in a sample of patients (n = 160) who underwent RT for breast or prostate cancer. At each time point, an exploratory factor analysis was done to determine the number of symptom clusters (i.e., symptom factors) based on the MSAS symptom severity ratings. MAIN RESULTS: The majority of the patients were male and married with a mean age of 61.1 years. The five symptoms with the highest occurrence rates across all three time points were lack of energy, pain, difficulty sleeping, feeling drowsy, and sweats. Although the number of symptoms and the specific symptoms within each symptom cluster were not identical across the three time points, three relatively similar symptom clusters (i.e., "mood-cognitive" symptom cluster, "sickness-behavior" symptom cluster, "treatment-related", or "pain" symptom cluster) were identified in this sample. The internal consistency coefficients for the mood-cognitive symptom cluster and sickness-behavior symptom cluster were adequate at > or =0.68. CONCLUSIONS: Three relatively stable symptom clusters were found across RT. The majority of the symptom cluster severity scores were significantly higher in patients with breast cancer compared to patients with prostate cancer.

Preliminary evidence of a genetic association between tumor necrosis factor alpha and the severity of sleep disturbance and morning fatigue.

Although fatigue and sleep disturbance are prevalent symptoms in oncology patients and their family caregivers, little is known about the factors that contribute to interindividual variability in symptom severity ratings as well as in their underlying biological mechanisms. In this study, we sought to determine whether a functional genetic variation in a prominent proinflammatory cytokine, tumor necrosis factor-alpha (TNFA-308G>A [rs1800629] promoter polymorphism) was associated with overall ratings of sleep disturbance and fatigue as well as with the trajectories of these symptoms. Over 6 months, participants completed standardized measures of sleep disturbance and fatigue. Multiple linear regression was used to assess the effect of the TNFA genotype and other covariates on mean sleep disturbance and fatigue scores. Hierarchical linear modeling was used to determine the effect of TNFA genotype on the trajectories of these symptoms. Common allele homozygotes reported higher levels of sleep disturbance (p=.09) and morning fatigue (p=.02) than minor allele carriers. Multivariate analyses demonstrated that age and genotype were predictors of both mean symptom scores and the trajectories of these symptoms. Findings provide preliminary evidence of an association between a functional promoter polymorphism in the TNFA gene and the severity of sleep disturbance and morning fatigue in oncology patients and their family caregivers.

Trajectories of fatigue in family caregivers of patients undergoing radiation therapy for prostate cancer.

Predictors of and trajectories for evening and morning fatigue were evaluated in family caregivers of oncology patients using hierarchical linear modeling. Evening fatigue trajectory fit a quadratic model. Predictors included baseline sleep disturbances in family caregivers and baseline evening fatigue in patients. Morning fatigue trajectory fit a linear model. Predictors were baseline trait anxiety, levels of perceived family support, and baseline morning fatigue in patients. Findings suggest considerable inter-individual variability in the trajectories of evening and morning fatigue. Evaluating family caregivers for sleep disturbance, anxiety, and poor family support, as well as high levels of patient fatigue, could identify those family caregivers at highest risk for sustained fatigue trajectories.

Trajectories of fatigue in men with prostate cancer before, during, and after radiation therapy.

Fatigue is the most common and distressing symptom reported by patients undergoing radiation therapy (RT). However, limited information is available on the trajectories of fatigue, as well as on the predictors of interindividual variability in fatigue. This study evaluated a sample of patients who underwent RT for prostate cancer to examine how ratings of evening and morning fatigue changed from the time of simulation to four months after the completion of RT and to investigate whether specific patient, disease, and symptom characteristics predicted the initial levels of fatigue and/or characteristics of the trajectories of evening and morning fatigue. Using hierarchical linear modeling, a large amount of interindividual variability was demonstrated in the trajectories of evening and morning fatigue. Findings from this study suggest that younger men with a higher level of fatigue at the time of the simulation visit were at increased risk for higher levels of evening and morning fatigue over the course of RT. In addition, the level of morning fatigue over the course of RT appears to depend on the patient's level of depression at the time of the simulation visit. In future studies, the use of hierarchical linear modeling as an analytic tool will assist in the identification of patients who are most at risk for prolonged fatigue trajectories. This type of analysis may lead to the identification of subgroups of patients who are at higher risk for negative outcomes and who require different types of interventions for the fatigue associated with RT.

Prognostic factors and grading systems for overall survival in patients treated with radiosurgery for brain metastases: variation by primary site.

OBJECT: The authors conducted a study to determine whether prognostic factors and the applicability of prognostic systems vary by primary tumor site in patients treated with radiosurgery for brain metastases. METHODS: The authors evaluated data obtained in patients who underwent radiosurgery with or without whole-brain radiotherapy (WBRT) from 1991 to 2005 for newly diagnosed brain metastases. Four groups were analyzed: 1) all primary sites combined, 2) breast, 3) lung, and 4) melanoma primary sites. Kaplan-Meier, log-rank, Cox proportional hazard uni- and multivariate analysis, and recursive partitioning analysis (RPA) were used to assess prognostic factors and 4 prognostic systems: Radiation Therapy Oncology Group (RTOG) RPA, Graded Prognostic Assessment (GPA), basic score for brain metastases (BSBM), and the newly proposed Golden grading system (GGS). The GGS divides patients into 4 prognostic groups by age >or= 65 years, Karnofsky Performance Scale (KPS) score < 70, and known presence of extracranial metastases. RESULTS: Data acquired in 479 newly diagnosed patients with 1664 lesions were analyzed. The median survival time from diagnosis of brain metastases was 12.1 months; the median follow-up was 25.4 months in 73 patients who were censored. Survival and prognostic factors were equivalent for 369 patients treated with radiosurgery compared with 110 patients treated with radiosurgery and WBRT, so these subsets were combined. Multivariate analysis of all primary sites combined demonstrated age < 65 years, KPS score >or= 70, no known extracranial metastases, and or= 70 years, primary tumor control, and 3 metastases was 15.6 and 16.9 months, respectively, for breast, 16.5 and 11.3 months for lung, and 9.0 and 5.7 months for melanoma. Analysis of the 4 prognostic systems (RTOG RPA, BSBM, GPA, and GGS) showed that each prognostic system's clinical applicability varied depending on primary tumor site. The RPA confirmed that GGS and primary tumor site are significant variables for prognosis. CONCLUSIONS: Favorable prognostic factors for patients with newly diagnosed brain metastases treated with radiosurgery vary by primary site. The 4 prognostic grading systems analyzed were applicable to different primary sites depending on which prognostic factors each individual system incorporated. Therefore, the authors recommend further development and use of primary-specific prognostic systems.

Long-term outcome and toxicities of intraoperative radiotherapy for high-risk neuroblastoma.

PURPOSE: To review a historical cohort of consecutively accrued patients with high-risk neuroblastoma treated with intraoperative radiotherapy (IORT) to determine the therapeutic effect and late complications of this treatment. METHODS AND MATERIALS: Between 1986 and 2002, 31 patients with newly diagnosed high-risk neuroblastoma were treated with IORT as part of multimodality therapy. Their medical records were reviewed to determine the outcome and complications. Kaplan-Meier probability estimates of local control, progression-free survival, and overall survival at 36 months after diagnosis were recorded. RESULTS: Intraoperative radiotherapy to the primary site and associated lymph nodes achieved excellent local control at a median follow-up of 44 months. The 3-year estimate of the local recurrence rate was 15%, less than that of most previously published series. Only 1 of 22 patients who had undergone gross total resection developed recurrence at the primary tumor site. The 3-year estimate of local control, progression-free survival, and overall survival was 85%, 47%, and 60%, respectively. Side effects attributable to either the disease process or multimodality treatment were observed in 7 patients who developed either hypertension or vascular stenosis. These late complications resulted in the death of 2 patients. CONCLUSIONS: Intraoperative radiotherapy at the time of primary resection offers effective local control in patients with high-risk neuroblastoma. Compared with historical controls, IORT achieved comparable control and survival rates while avoiding many side effects associated with external beam radiotherapy in young children. Although complications were observed, additional analysis is needed to determine the relative contributions of the disease process and specific components of the multimodality treatment to these adverse events.

Glomus tumors treated with stereotactic radiosurgery: A retrospective study.

BACKGROUND: Glomus tumors are difficult to manage surgically because they are vascular tumors that are topographically associated with important vascular and neuronal structures. Hence, there is a strong risk of incomplete resection and a high morbidity rate. In addition, they grow slowly. Recent treatments have increasingly involved a combination of surgical resection and radiosurgery. We present our experience in treating glomus tumors of the skull base with stereotactic radiosurgery as an upfront therapy. METHODS: We analyzed data from 13 consecutive patients with glomus tumors that were initially treated with stereotactic radiosurgery in our institute from February 2010 to April 2012. The tumor control rate, resolution of symptoms, and the complication rate were tabulated. RESULTS: All patients were female with a median age of 63 (mean 62.7+/-14.6 years). The median treatment dose was 25.8 Gy (27.6 Gy +/- 9.5 Gy) and the median tumor volume 10.4 mL (9.2 +/- 6.5). The median follow-up was 47.4 months (51.8+/-11.2 months, range 31-74). The tumor control rate was 92.3%; 46.7% of the patients had noticeable tumor shrinkage. This happened at a median interval of 17 months (18.7+/-6.8) after treatment. Most patients with tinnitus had resolution of their symptoms (87.5%). Four patients presented with new symptoms and four patients with worsening of pre-existing symptoms. The time course of symptomatic improvement followed that of tumor size reduction. However, there was no statistical correlation between the amount of tumor reduction and symptomatic relief. CONCLUSION: Stereotactic radiosurgery (SRS) is an effective upfront treatment option in the management of glomus tumors.

The role of up-front radiation therapy for incompletely resected pediatric WHO grade II low-grade gliomas.

The purpose of this study was to assess the impact of early radiation therapy and extent of surgical resection on progression-free survival (PFS) and overall survival (OS) in children with WHO grade II low-grade gliomas (LGGs). We conducted a historical cohort study of 90 patients, ages 21 or younger, diagnosed with WHO grade II LGGs between 1970 and 1995. Median follow-up for surviving patients was 9.4 years (range, 0.5-22.6 years). Tests for variables correlating with OS and PFS were conducted by using log-rank tests and Cox proportional hazards models. Eleven patients underwent gross total resections (GTRs), 43 had subtotal resections, and 34 underwent biopsy only at diagnosis. Two patients underwent biopsy at time of recurrence. Of the 90 patients, 52 received radiation as part of their initial therapy following diagnosis (early-RT group). The overall five-year PFS and OS rates +/- SE were 56% +/- 5% and 90% +/- 3%, respectively. Ten-year PFS and OS rates were 42% +/- 6% and 81% +/- 5%, respectively. For patients older than three years and without GTRs, administration of early radiation did not appear to influence PFS or OS (P = 0.98 and P = 0.40, respectively; log-rank test). This was confirmed by multivariate analyses (P = 0.95 and P = 0.33 for PFS and OS, respectively). Of the 11 patients with GTRs, disease progressed in only two, and all were alive with no evidence of disease at last follow-up. Patients who underwent GTRs had significantly longer PFS (P = 0.02), but did not have significantly improved OS. Excellent long-term survival rates were achieved for children with WHO grade II LGGs. We were unable to demonstrate a benefit for administering radiation as part of initial treatment. An outcome benefit was seen with greater extent of resection.

High failure rate in spinal ependymomas with long-term follow-up.

Data on spinal ependymomas are sparse, and prognostic factors remain controversial. The primary aim of this study is to review a historical cohort, with large patient numbers and long follow-up, and provide estimates of time to progression (TTP) and survival after progression. As a secondary aim, we assess the effects of potential prognostic variables. Thirty-seven patients with spinal cord ependymomas received postoperative radiation therapy from 1955 to 2001. The influences of radiation dose, extent of resection, Karnofsky performance score, tumor location, and multifocality were assessed in univariate analyses by using the Cox proportional hazards model. The median follow-up for patients who did not fail was 121 months (range, 8-312 months). Kaplan-Meier estimates of 5-, 10-, and 15-year percentage progression free are 75%+/-7.4%, 50%+/-9.1%, and 46%+/-9.3%, respectively. Median TTP, for those who recurred, is 68 months (range, 2-324 months), with 12 of 21 failures occurring after five years. Of the prognostic factors examined, only greater extent of resection significantly correlated with longer TTP (P=0.02). Local relapse rates for spinal ependymomas are higher than previously cited, with a large proportion of failures occurring more than five years after diagnosis. Extensive surgical resection correlates with longer time to recurrence, and we thus recommend maximal excision while avoiding surgical morbidity. The overall high rate of recurrence leads us to recommend radiation to doses of 45 to 54 Gy for all patients who do not have gross total resections, and long, close follow-up.

A phase II study of concurrent temozolomide and cis-retinoic acid with radiation for adult patients with newly diagnosed supratentorial glioblastoma.

PURPOSE: This Phase II study was designed to determine the median survival time of adults with supratentorial glioblastoma treated with a combination of temozolomide (TMZ) and 13-cis-retinoic acid (cRA) given daily with conventional radiation therapy (XRT). METHODS AND MATERIALS: This was a single arm, open-labeled, Phase II study. Patients were treated with XRT in conjunction with cRA and TMZ. Both drugs were administered starting on Day 1 of XRT, and chemotherapy cycles continued after the completion of XRT to a maximum of 1 year. RESULTS: Sixty-one patients were enrolled in the study. Time to progression was known for 55 patients and 6 were censored. The estimated 6-month progression-free survival was 38% and the estimated 1-year progression-free survival was 15%. Median time to progression was estimated as 21 weeks. The estimated 1-year survival was 57%. The median survival was 57 weeks. CONCLUSIONS: The combined therapy was relatively well tolerated, but there was no survival advantage compared with historical studies using XRT either with adjuvant nitrosourea chemotherapy, with TMZ alone, or with the combination of TMZ and thalidomide. Based on this study, cRA does not seem to add a significant synergistic effect to TMZ and XRT.

Cytokine gene associations with self-report ratings of morning and evening fatigue in oncology patients and their family caregivers.

The purpose of this study was to evaluate for differences in variations in pro- and anti-inflammatory cytokine genes between participants who were classified as having low and high levels of morning and evening fatigue and to evaluate for differences in phenotypic characteristics between these two groups. In a sample of 167 oncology outpatients with breast, prostate, lung, or brain cancer and 85 of their family caregivers, growth mixture modeling was used to identify latent classes of individuals based on ratings of morning and evening fatigue obtained prior to, during, and for 4 months following completion of radiation therapy. Differences in single nucleotide polymorphisms and haplotypes in 15 cytokine genes were evaluated between the latent classes. Multiple logistic regression was used to assess the effect of phenotypic and genotypic characteristics on morning and evening fatigue class membership. Associations were found between morning fatigue and number of comorbidities as well as variations in tumor necrosis factor alpha (TNFA) rs1800629 and rs3093662. Evening fatigue was associated with caring for children at home and variations in interleukin 4 (IL4) rs2243248 and TNFA rs2229094. Younger age and lower performance status were associated with both morning and evening fatigue. These findings suggest that inflammatory mediators are associated with the development of morning and evening fatigue. However, because different phenotypic characteristics and genomic markers are associated with diurnal variations in fatigue, morning and evening fatigue may be distinct but related symptoms.

Permanent iodine 125 brachytherapy in patients with progressive or recurrent glioblastoma multiforme.

This study reports the initial experience at the University of California San Francisco (UCSF) with tumor resection and permanent, low-activity iodine 125 (125I) brachytherapy in patients with progressive or recurrent glioblastoma multiforme (GM) and compares these results to those of similar patients treated previously at UCSF with temporary brachytherapy without tumor resection. Thirty-eight patients with progressive or recurrent GM were treated at UCSF with repeat craniotomy, tumor resection, and permanent, low-activity 125I brachytherapy between June 1997 and May 1998. Selection criteria were Karnofsky performance score > or =60, unifocal, contrast-enhancing, well-circumscribed progressive or recurrent GM that was judged to be completely resectable, and no evidence of leptomeningeal or subependymal spread. The median brachytherapy dose 5 mm exterior to the resection cavity was 300 Gy (range, 150-500 Gy). One patient was excluded from analysis. Median survival was 52 weeks from the date of brachytherapy. Age, Karnofsky performance score, and preimplant tumor volume were all statistically significant on univariate analyses. Multivariate analysis for survival showed only age to be significant. Median time to progression was 16 weeks. Both univariate and multivariate analysis of freedom from progression showed only preoperative tumor volume to be significant. Comparison to temporary brachytherapy patients showed no apparent difference in survival time. Chronic steroid requirements were low in patients with minimal postoperative residual tumor. We conclude that permanent 125I brachytherapy for recurrent or progressive GM is well tolerated. Survival time was comparable to that of a similar group of patients treated with temporary brachytherapy.

Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme.

PURPOSE: The chemotherapeutic agent temozolomide (TMZ) and the antiangiogenic agent thalidomide have both demonstrated antitumor activity in patients with recurrent malignant glioma. The objectives of this study were to determine if the combined strategy of these oral agents with radiation therapy (RT) is associated with an improved median survival of patients with newly diagnosed glioblastoma multiforme and to evaluate toxicity. METHODS AND MATERIALS: Sixty-seven patients were enrolled in this trial. Radiotherapy parameters were a total dose of 60 Gy delivered in 2 Gy fractions over 6 weeks. Temozolomide was administered starting the first day of RT at 150 mg/m(2) daily for 5 days every 4 weeks for the first cycle and escalated to a maximum dose of 200 mg/m(2). Thalidomide was started on Day 7 of RT at 200 mg and escalated by 100-200 mg every 1-2 weeks depending on patient tolerance, to a maximum of 1,200 mg daily. RESULTS: Sixty-one patients have progressed, with a median time to progression of 22 weeks. Fifty-six patients have died, and the median survival was 73 weeks. CONCLUSIONS: This strategy of combination TMZ, thalid and RT was relatively well tolerated with favorable survival outcome for patients with GM when compared to patients not treated with adjuvant chemotherapy and similar to those who have received nitrosourea adjuvant chemotherapy. It is unclear the added advantage thalid has in combination with TMZ for this patient population.

Comparison of intensity-modulated radiosurgery with gamma knife radiosurgery for challenging skull base lesions.

PURPOSE: To quantitatively compare intensity-modulated radiosurgery (IMRS) using 3-mm mini-multileaf collimation with gamma knife radiosurgery (GKRS) plans for irregularly shaped skull base lesions in direct proximity to organs at risk (OAR). METHODS AND MATERIALS: Ten challenging skull base lesions originally treated with GKRS were selected for comparison with IMRS using inverse treatment planning and 3-mm mini-multileaf collimation operating in step-and-shoot delivery mode. The lesions ranged in volume from 1.6 to 32.2 cm(3) and were treated with 9-20 GK isocenters (mean 13.2). The IMRS plans were designed with the intent to, at minimum, match the GKRS plans with regard to OAR sparing and target coverage. For each case, IMRS plans were generated using 9 coplanar, 11 equally spaced noncoplanar, and 11 OAR-avoidant noncoplanar beams; the best of these approaches with respect to target conformality, sparing of OAR, and maintaining coverage was selected for comparison with the original GKRS plan. RESULTS: Assuming no patient motion or setup error, IMRS provided comparable target coverage and sparing of OAR and an improved conformity index at the prescription isodose contour but sometimes less conformity at lower isodose contours compared with the actual GKRS plan. All IMRS plans produced less target dose heterogeneity and shorter estimated treatment times compared with the GKRS plans. CONCLUSION: Compared with GKRS for complex skull base lesions, IMRS plans using a 3-mm mini-multileaf collimator achieved comparable or sometimes improved target coverage, conformity, and critical structure sparing with shorter estimated treatment times.

Metabolic imaging of low-grade gliomas with three-dimensional magnetic resonance spectroscopy.

PURPOSE: The role of radiotherapy (RT) seems established for patients with low-grade gliomas with poor prognostic factors. Three-dimensional (3D) magnetic resonance spectroscopy imaging (MRSI) has been reported to be of value in defining the extent of glioma infiltration. We performed a study examining the impact MRSI would have on the routine addition of 2-3-cm margins around MRI T2-weighted hyperintensity to generate the treatment planning clinical target volume (CTV) for low-grade gliomas. METHODS AND MATERIALS: Twenty patients with supratentorial gliomas WHO Grade II (7 astrocytomas, 6 oligoastrocytomas, 7 oligodendrogliomas) underwent MRI and MRSI before surgery. The MRI was contoured manually; the regions of interest included T2 hyperintensity and, if present, regions of contrast enhancement on T1-weighted images. The 3D-MRSI peak parameters for choline and N-acetyl-aspartate, acquired voxel-by-voxel, were categorized using a choline/N-acetyl-aspartate index (CNI), a tool for quantitative assessment of tissue metabolite levels, with CNI 2 being the lowest value corresponding to tumor. CNI data were aligned to MRI and displayed as 3D contours. The relationship between the anatomic and metabolic information on tumor extent was assessed by comparing the CNI contours and other MRSI-derived metabolites to the MRI T2 volume. RESULTS: The limitations in the size of the region "excited" meant that MRSI could be used to evaluate only a median 68% of the T2 volume (range 38-100%), leaving the volume T2c. The CNI 2 volume (median 29 cm(3), range 10-73) was contained totally within the T2c in 55% of patients. In the remaining patients, the volume of CNI 2 extending beyond the T2c was quite small (median 2.3 cm(3), range 1.4-5.2), but was not distributed uniformly about the T2c, extending up to 22 mm beyond it. Two patients demonstrated small regions of contrast enhancement corresponding to the regions of highest CNI. Other metabolites, such as creatine and lactate, seem useful for determining less and more radioresistant areas, respectively. CONCLUSION: Metabolically active tumor, as detected by MRSI, is restricted mainly to the T2 hyperintensity in low-grade gliomas, but can extend outside it in a limited and nonuniform fashion up to 2 cm. Therefore, a CTV including T2 and areas of CNI extension beyond the T2 hyperintensity would result in a reduction in the size and a change in the shape of the standard clinical target volumes generated by adding uniform margins of 2-3 cm to the T2 hyperintensity.

Phase II study of high central dose Gamma Knife radiosurgery and marimastat in patients with recurrent malignant glioma.

PURPOSE: To assess the outcome of high central dose Gamma Knife radiosurgery plus marimastat in patients with recurrent malignant glioma. METHODS AND MATERIALS: Twenty-six patients with recurrent malignant glioma were enrolled in a prospective Phase II study between November 1996 and January 1999. The radiosurgery dose was prescribed at the 25-30% isodose surface to increase the dose substantially within the tumor's presumably hypoxic core. Marimastat was administered after radiosurgery to restrict regional tumor progression. Survival was compared with that of historical patients treated at our institution with standard radiosurgery. RESULTS: The median times to progression after radiosurgery for Grade 3 and 4 patients was 31 and 15 weeks, respectively. The corresponding median survival time after radiosurgery was 68 and 38 weeks. The median survival time after radiosurgery in the historical patients was 59 and 44 weeks. CONCLUSION: The dual strategies of using high central dose radiosurgery to overcome tumor hypoxia together with marimastat to inhibit local tumor invasion may offer a small survival advantage for recurrent Grade 3 tumors; they do not offer an advantage for recurrent Grade 4 tumors.

Radiation therapy for intracranial germ cell tumors.

PURPOSE: To review the combined experiences of University of California, San Francisco, and Stanford University Medical Center in the treatment of intracranial germ cell tumors (GCT) and to assess the impact of craniospinal radiation (CSI) on patterns of relapse, progression-free survival (PFS), and overall survival (OS). PATIENTS AND METHODS: Ninety-three patients received radiation for newly diagnosed intracranial GCTs, including 49 germinomas, 16 nongerminomatous GCTs (NGGCT), and 28 with no biopsy. Median follow-up for surviving patients was 4.5 years (range 0.25-34). Tests for variables correlating with OS and PFS were conducted using Cox proportional hazards model. RESULTS: Five-year PFS and OS rates were 60% +/- 15% and 68% +/- 14% for patients with NGGCT and 88% +/- 5% and 93% +/- 4% for those with germinoma. Of 6 patients with localized NGGCT who did not receive CSI, 1 experienced an isolated spinal recurrence but was salvaged. Of 41 patients with localized germinoma, 6 who received CSI and 35 who did not, no isolated spinal cord relapses occurred. Twenty-one patients with localized germinoma received neither CSI nor whole brain radiation. Of these, none of 18 with ventricular radiation relapsed. One of 3 patients with primary tumor radiation relapsed intracranially but had only received 11 Gy at initial treatment. On multivariate analysis, germinoma histology but not CSI correlated with improved PFS and OS. CONCLUSION: CSI is not indicated in the treatment of localized germinomas. For patients with localized germinomas treated with radiation alone, we recommend ventricular irradiation followed by primary tumor boost to a total of 45-50 Gy.

Surgical resection and permanent brachytherapy for recurrent atypical and malignant meningioma.

OBJECTIVE: Recurrent atypical and malignant meningiomas are difficult to treat successfully. Chemotherapy to date has been unsuccessful, and radiosurgery is limited to smaller tumors. Reoperation alone provides limited tumor control and limited prolonged survival. The addition of brachytherapy at the time of operation is an option. Here, we report the results of our series of patients with recurrent malignant meningioma treated with resection and brachytherapy with permanent low-dose (125)I. METHODS: The charts of patients in our database with recurrent atypical and malignant meningiomas treated by surgical resection and permanent (125)I brachytherapy at the University of California, San Francisco, between 1988 and 2002 were selected for this study. Calculations of disease-free survival and overall survival curves were made by the Kaplan-Meier actuarial method. Univariate analysis between Kaplan-Meier curves was based on the log-rank statistic, with a significance level set at a value of P

Stereotactic radiosurgery for pediatric intracranial arteriovenous malformations: the University of California at San Francisco experience.

OBJECT: Stereotactic radiosurgery for arteriovenous malformations (AVMs) is an accepted treatment option, but few reports have been published on the results of this treatment in children. In this study the authors describe a series of pediatric patients with a minimum follow-up duration of 36 months. METHODS: From 1991 to 1997, 40 children (26 boys and 14 girls) with AVMs were treated with radiosurgery at the University of California at San Francisco (UCSF). Follow-up information was available for 31 children (20 boys and 11 girls) in whom the median age at initial treatment was 11.2 years (range 3.4-17.5 years). The median follow-up duration was 60 months (range 6-99 months). Sixteen percent of the AVMs were Spetzler-Martin Grade II; 68%, Grade III; 10%, Grade IV; and 6%, Grade V. The mean volume of the AVMs was 5.37 cm3 and the median volume was 1.6 cm3. The mean marginal dose of radiation was 16.7 Gy and the median dose was 18 Gy (range 12-19 Gy). Angiography performed in 26 children confirmed obliteration of the AVM nidus in nine patients (35%), partial response in 16 patients (62%), and no response in one patient (4%). In five patients who refused angiography, magnetic resonance (MR) imaging revealed obliteration in two patients and partial response in three patients, bringing the overall obliteration rate associated with initial radiosurgery to 35%. Logistic regression analysis confirmed a significant correlation between marginal dose prescription and response (p = 0.025); in AVMs that received at least 18 Gy there was a 10-fold increase in the obliteration rate (63%) over AVMs that received a lower dose. Lesions smaller than 3 cm3 were associated with a six-fold increased obliteration rate (53%) over lesions larger than 3 cm3 (8%), but AVM volume was not a statistically significant predictor of response (p = 0.09). Twelve patients have since undergone repeated radiosurgery and are currently being followed up with serial MR imaging studies (in five cases, the AVM is now obliterated). During the follow-up period (1918 patient-months) there were eight hemorrhages in five patients, with a cumulative posttreatment hemorrhage rate of 3.2%/patient/year in the 1st year and a rate of 4.3%/patient/year over the first 3 years. There were two permanent neurological complications (6%) and no deaths in this study. CONCLUSIONS: The lower overall obliteration rate reported in this series is most likely due to the larger mean AVM volumes treated at UCSF as well as conservative dose-volume prescriptions delivered to children. Significantly higher obliteration rates were observed when a marginal radiation dose of at least 18 Gy was delivered. The permanent complication rate is low and should encourage those treating children to use doses similar to those used in adults.