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Background: The role of stereotactic radiosurgery (SRS) for recurrent glioblastoma and the radionecrosis risk in this setting remain unclear., Objective: To perform a large retrospective study to help inform proper indications, efficacy, and anticipated complications of SRS for recurrent glioblastoma., Methods: We retrospectively analyzed patients who underwent Gamma Knife SRS between 1991 and 2013. We used the partitioning deletion/substitution/addition algorithm to identify potential predictor covariate cut points and Kaplan-Meier and proportional hazards modeling to identify factors associated with post-SRS and postdiagnosis survival., Results: One hundred seventy-four glioblastoma patients (median age, 54.1 years) underwent SRS a median of 8.7 months after initial diagnosis. Seventy-five percent had 1 treatment target (range, 1-6), and median target volume and prescriptions were 7.0 cm 3 (range, 0.3-39.0 cm 3 ) and 16.0 Gy (range, 10-22 Gy), respectively. Median overall survival was 10.6 months after SRS and 19.1 months after diagnosis. Kaplan-Meier and multivariable modeling revealed that younger age at SRS, higher prescription dose, and longer interval between original surgery and SRS are significantly associated with improved post-SRS survival. Forty-six patients (26%) underwent salvage craniotomy after SRS, with 63% showing radionecrosis or mixed tumor/necrosis vs 35% showing purely recurrent tumor. The necrosis/mixed group had lower mean isodose prescription compared with the tumor group (16.2 vs 17.8 Gy; P = .003) and larger mean treatment volume (10.0 vs 5.4 cm 3 ; P = .009)., Conclusion: Gamma Knife may benefit a subset of focally recurrent patients, particularly those who are younger with smaller recurrences. Higher prescriptions are associated with improved post-SRS survival and do not seem to have greater risk of symptomatic treatment effect., (Copyright © 2016 by the Congress of Neurological Surgeons)

Standard treatment for Glioblastoma Multiforme (GBM) consists of a combination of chemotherapy and radiation therapy followed by adjuvant chemotherapy. While the optimal dose of radiation therapy has been established, significant variability in volume of tissue irradiated exists. In this article we review the current guidelines, patterns of care, patterns of failure, imaging advances and toxicity related to radiation therapy volumes in the treatment of GBM., (Copyright © 2014. Published by Elsevier Inc.)

This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m(2) daily during RT and then adjuvantly at 200 mg/m(2) daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.

Purpose: This open-label, prospective, single-arm, phase II study combined erlotinib with radiation therapy (XRT) and temozolomide to treat glioblastoma multiforme (GBM) and gliosarcoma. The objectives were to determine efficacy of this treatment as measured by survival and to explore the relationship between molecular markers and treatment response., Patients and Methods: Sixty-five eligible adults with newly diagnosed GBM or gliosarcoma were enrolled. We intended to treat patients not currently treated with enzyme-inducing antiepileptic drugs (EIAEDs) with 100 mg/d of erlotinib during XRT and 150 mg/d after XRT. Patients receiving EIAEDs were to receive 200 mg/d of erlotinib during XRT and 300 mg/d after XRT. After XRT, the erlotinib dose was escalated until patients developed tolerable grade 2 rash or until the maximum allowed dose was reached. All patients received temozolomide during and after XRT. Molecular markers of epidermal growth factor receptor (EGFR), EGFRvIII, phosphatase and tensin homolog (PTEN), and methylation status of the promotor region of the MGMT gene were analyzed from tumor tissue. Survival was compared with outcomes from two historical phase II trials., Results: Median survival was 19.3 months in the current study and 14.1 months in the combined historical control studies, with a hazard ratio for survival (treated/control) of 0.64 (95% CI, 0.45 to 0.91). Treatment was well tolerated. There was a strong positive correlation between MGMT promotor methylation and survival, as well as an association between MGMT promotor-methylated tumors and PTEN positivity shown by immunohistochemistry with improved survival., Conclusion: Patients treated with the combination of erlotinib and temozolomide during and following radiotherapy had better survival than historical controls. Additional studies are warranted.

Purpose: To evaluate the feasibility of gross total resection and permanent I-125 brachytherapy followed by hyperfractionated radiotherapy for patients with newly diagnosed glioblastoma., Methods and Materials: From April 1999 to May 2002, 21 patients with glioblastoma multiforme were enrolled on a Phase I protocol investigating planned gross total resection and immediate placement of permanent I-125 seeds, followed by postoperative hyperfractionated radiotherapy to a dose of 60 Gy at 100 cGy b.i.d., 5 days per week. Median age and Karnofsky performance status were 50 years (range, 32-65 years) and 90 (range, 70-100), respectively. Toxicity was assessed according to Radiation Therapy Oncology Group criteria., Results: Eighteen patients completed treatment according to protocol. The median preoperative tumor volume on magnetic resonance imaging was 18.6 cm(3) (range, 4.4-41.2 cm(3)). The median brachytherapy dose measured 5 mm radially outward from the resection cavity was 400 Gy (range, 200-600 Gy). Ten patients underwent 12 reoperations, with 11 of 12 reoperations demonstrating necrosis without evidence of tumor. Because of high toxicity, the study was terminated early. Median progression-free survival and overall survival were 57 and 114 weeks, respectively, but not significantly improved compared with historical patients treated at University of California, San Francisco, with gross total resection and radiotherapy without brachytherapy., Conclusions: Treatment with gross total resection and permanent I-125 brachytherapy followed by hyperfractionated radiotherapy as performed in this study results in high toxicity and reoperation rates, without demonstrated improvement in survival.

Glioblastoma multiforme (GBM) tumors almost invariably recur despite initial treatments. Correct diagnosis using a variety of imaging techniques and the involvement of a multidisciplinary tumor board are critical for evaluating each stage of a patient's progression and determining optimal management. Standard therapies for recurrence generally include repeated resection, radiation therapy, chemotherapy, and supportive care; however, salvage therapy must be highly individualized, and not all patients are eligible for every type of standard therapy. Factors such as the size and location of the tumor, previous treatment, and general health of the patient must be taken into consideration. Although standard therapies can prolong a patient's duration of survival, the median survival time for patients with recurrent GBM is usually less than 1 year. Experimental targeted drug therapies have been developed to inhibit aberrant cell-signaling pathways involved in tumorigenesis, and enrolling patients in clinical trials using these therapies is another option for treatment of recurrent GBM. The use of these novel therapies is often confined to large research institutions, but the severe limitations of standard treatment options make it important to highlight the potential of experimental therapies. In this paper the authors outline standard therapies and review the emerging role of targeted drug therapy in the treatment of recurrent GBM.

The prognostic significance of the histologic type and grade of gliomas at initial surgery is well established, but the value of histologic findings in resections after radiotherapy is unclear. Despite this uncertainty, pathologic interpretation of specimens after radiotherapy influences immediate treatment decisions. It is important to determine if, and to what extent, treatment decisions should be based on this information. We aimed to determine the prognostic value of pathologic evaluation in postradiation specimens from 54 patients with similar clinical features who underwent a second surgery for the treatment of radiologic worsening after external beam radiotherapy. We categorized the specimens from the second surgery as either recurrent tumor (category 1) or radionecrosis (category 2). Patients in category 1 had actively proliferating neoplasms with classical features of glioblastoma, whereas patients in category 2 had no evidence of tumor in their surgical specimens. Cases in which a clear-cut definition could not be made were labeled indeterminate (category 3). Despite the morphological evidence of tumor, there were no significant differences between categories 1 and 2 in any of the survival parameters tested. The only difference between groups was higher frequency of iodine 125 (125I) placement at second surgery in category 1 patients (P <.028). Patients in category 1 with or without 125I treatment had similar survival characteristics. We conclude that histopathologic evaluation of postradiotherapy specimens was not helpful in predicting outcome or dictating further management. A comprehensive prospective study with advanced radiologic, pathologic, and molecular analyses may be more useful to determine prognostically valuable parameters.

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.

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.

Objective: Advanced age is a strong predictor of shorter survival in patients with glioblastoma multiforme (GM), especially for those who receive multimodality treatment. Radiographically assessed tumor response to external beam radiation therapy is an important prognostic factor in GM. We hypothesized that older GM patients might have more radioresistant tumors., Methods: We studied radiographically assessed response to external beam radiation treatment (five-level scale) in relation to age and other prognostic factors in a cohort of 301 GM patients treated on two prospective clinical protocols. A total of 223 patients (74%) were assessable for radiographically assessed radiation response. A proportional odds ordinal regression model was used for univariate and multivariate analysis., Results: Younger age (P = 0.006), higher Karnofsky Performance Scale score before radiotherapy (P = 0.027), and more extensive surgical resection (P = 0.028) predicted better radiation response in univariate analyses. Results were similar when clinical criteria were used to classify an additional 61 patients without radiographically assessed radiation response (stable versus progressive disease). In multivariate analyses, age and extent of resection were significant independent predictors of radiation response (P < 0.05); Karnofsky Performance Scale score was of borderline significance (P = 0.07)., Conclusion: Older GM patients are less likely to have good responses to postoperative external beam radiation therapy. Karnofsky Performance Scale score before radiation treatment and extent of surgical resection are additional predictors of radiographically assessed radiation response in GM.

Purpose: Recent studies have suggested relative radioresistance in glioblastoma multiforme (GM) tumors in older patients, consistent with their shorter survival. Two common molecular genetic abnormalities in GM are age related: epidermal growth factor receptor (EGFR) overexpression in older patients and p53 mutations in younger patients. We tested whether these abnormalities correlated with clinical heterogeneity in GM response to radiation treatment., Methods and Materials: Radiographically assessed radiation response (5-level scale) was correlated with EGFR immunoreactivity, p53 immunoreactivity, and p53 exon 5-8 mutation status in 170 GM patients treated using 2 prospective clinical protocols. Spearman rank correlation and proportional-odds ordinal regression were used for univariate and multivariate analysis., Results: Positive EGFR immunoreactivity predicted poor radiographically assessed radiation response (p = 0.046). Thirty-three percent of tumors with no EGFR immunoreactivity had good radiation responses (>50% reduction in tumor size by CT or MRI), compared to 18% of tumors with intermediate EGFR staining and 9% of tumors with strong staining. There was no significant relationship between p53 immunoreactivity or mutation status and radiation response. Significant relationships were noted between EGFR score and older age and between p53 score or mutation status and younger age., Conclusion: The observed relative radioresistance of some GMs is associated with overexpression of EGFR.

Purpose: To report the results of a prospective Phase III trial for patients with newly diagnosed glioblastoma multiforme (GBM), treated with either accelerated hyperfractionated irradiation with or without difluromethylornithine (DFMO) or standard fractionated irradiation with or without DFMO., Methods and Materials: Adult patients with newly diagnosed GBM were registered and randomized following surgery to one of 4 treatment arms: Arm A, accelerated hyperfractionation alone using 2 fractions a day of 1.6 Gy to a total dose of 70.4 Gy in 44 fractions; Arm B, accelerated hyperfractionation as above plus DFMO 1.8 gm/m2 by mouth every 8 h beginning one week before radiation until the last fraction was given; Arm C, single-fraction irradiation of 1.8 Gy/day to 59.4 Gy; Arm D, single-fraction irradiation as in Arm C plus DFMO given as in Arm B. Patients were followed for progression-free survival (PFS) and overall survival (OS), as well as for toxicity. Eligibility required histologically proven GBM, age > or =18, Karnofsky performance status (KPS) > or =60, and no prior chemotherapy or radiotherapy. Adjuvant chemotherapy was not used in this protocol., Results: A total of 231 eligible patients were enrolled. There were 95 men and 136 women with a median age of 57 years, and median KPS of 90. Extent of resection was total in 23, subtotal in 152, and biopsy only in 56 patients. The 4 arms were balanced with respect to age, KPS, and extent of resection. Times to event measurements are from date of diagnosis. Median OS and PFS were 40 and 19 weeks for Arm A; 42 and 22 weeks for Arm B; 37 and 16 weeks for Arm C; and 44 and 19 weeks for Arm D (p = 0.48 for survival; p = 0.32 for PFS). Comparison of the 2 arms treated with DFMO to the 2 arms without DFMO revealed no difference in OS (37 weeks vs. 42 weeks, p = 0.12) or PFS and thus no benefit to the use of DFMO. Comparison of the 2 standard fractionation arms to the 2 accelerated hyperfractionation arms also resulted in no difference in OS (42 weeks vs. 41 weeks, p = 0.75) or PFS, showing no benefit to accelerated hyperfractionated irradiation., Conclusion: In this prospective Phase III study, no survival or PFS benefit was seen with accelerated hyperfractionated irradiation to 70.4 Gy, nor was any benefit seen with DFMO as a radiosensitizer. Standard fractionated irradiation to 59.4 Gy remains the treatment of choice for newly diagnosed patients with glioblastoma multiforme.

Objective: The goal of this study was to investigate the use of proton magnetic resonance spectroscopic imaging as a prognostic indicator in gamma knife radiosurgery of recurrent gliomas., Methods: Thirty-six patients with recurrent gliomas were studied with proton magnetic resonance spectroscopic imaging at the time of radiosurgery, and with conventional magnetic resonance imaging examinations at regular time intervals until the initiation of a new treatment strategy. Patients were categorized on the basis of their initial spectroscopic results, and their performance was assessed in terms of change in contrast-enhancing volume, time to further treatment, and survival., Results: The trends in the overall population were toward more extensive increase in the percent contrast-enhancing volume, a decreased time to further treatment, and a reduced survival time for patients with more extensive initial metabolic abnormalities. Statistical analysis of the subpopulation of patients with glioblastoma multiforme found a significant increase in relative contrast-enhancing volume (P < 0.01, Wilcoxon signed-rank test), a decrease in time to further treatment (P < 0.01, log-rank test), and a reduction in survival time (P < 0.01, log-rank test) for patients with regions containing tumor-suggestive spectra outside the gamma knife target, compared with patients exhibiting spectral abnormalities restricted to the gamma knife target. Further studies are needed to establish statistical significance for patients with lower-grade lesions and to confirm the results observed in this study., Conclusion: The pretreatment spectroscopic results provided information that was predictive of outcome for this patient pool, both in local control (change in contrast-enhancing volume) and global outcome (time to further treatment and survival). This modality may have an important role in improving the selection, planning, and treatment process for glioma patients.

Purpose: To determine if adjuvant interstitial hyperthermia (HT) significantly improves survival of patients with glioblastoma undergoing brachytherapy boost after conventional radiotherapy., Methods and Materials: Adults with newly-diagnosed, focal, supratentorial glioblastoma < or = 5 cm in diameter were registered postoperatively on a Phase II/III randomized trial and treated with partial brain radiotherapy to 59.4 Gy with oral hydroxyurea. Those patients whose tumor was still implantable after teletherapy were randomized to brachytherapy boost (60 Gy at 0.40-0.60 Gy/h) +/- HT for 30 min immediately before and after brachytherapy. Time to progression (TTP) and survival from date of diagnosis were estimated using the Kaplan-Meier method., Results: From 1990 to 1995, 112 eligible patients were entered in the trial. Patient ages ranged from 21-78 years (median, 54 years) and KPS ranged from 70-100 (median, 90). Most commonly due to tumor progression or patient refusal, 33 patients were never randomized. Of the patients, 39 were randomized to brachytherapy ("no heat") and 40 to brachytherapy + HT ("heat"). By intent to treat, TTP and survival were significantly longer for "heat" than "no heat" (p = 0.04 and p = 0.04). For the 33 "no heat" patients and 35 "heat" patients who underwent brachytherapy boost, TTP and survival were significantly longer for "heat" than "no heat" (p = 0.045 and p = 0.02, respectively; median survival 85 weeks vs. 76 weeks; 2-year survival 31% vs. 15%). A multivariate analysis for these 68 patients adjusting for age and KPS showed that improved survival was significantly associated with randomization to "heat" (p = 0.008; hazard ratio 0.51). There were no Grade 5 toxicities, 2 Grade 4 toxicities (1 on each arm), and 7 Grade 3 toxicities (1 on "no heat" and 6 on the "heat" arm)., Conclusion: Adjuvant interstitial brain HT, given before and after brachytherapy boost, after conventional radiotherapy significantly improves survival of patients with focal glioblastoma, with acceptable toxicity.

Patients with primary brain tumors may be considered for several different treatments during the course of their disease. Assessments of disease progression and response to therapy are typically performed by visual interpretation of serial MRI examinations. Although such examinations provide useful morphologic information, they are unable to reliably distinguish active tumor from radiation necrosis. This poses a particular problem in the assessment of response to localized radiation therapies such as gamma knife radiosurgery. In this paper, we present methodology for evaluating changes in tissue morphology and metabolism based on serial volumetric MRI and magnetic resonance spectroscopic imaging (MRSI) examinations. Registration and quantitative analysis of these data provide measurements of the temporal and spatial distributions of gadolinium enhancement and of N-acetylasparate, choline, creatine, and lactate/lipid. The key features of this approach and the potential clinical benefits are illustrated by a detailed analysis of six serial MRI/MRSI examinations and three serial 1-[F-18] fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) studies on a patient with a recurrent anaplastic astrocytoma.

The utility of three-dimensional (3-D) proton magnetic resonance spectroscopy (1H-MRS) imaging for detecting metabolic changes after brain tumor therapy was assessed in a serial study of 58 total examinations of 12 patients with glioblastoma multiforme (GBM) who received brachytherapy. Individual proton spectra from the 3-D array of spectra encompassing the lesion showed dramatic differences in spectral patterns indicative of radiation necrosis, recurrent or residual tumor, or normal brain. The 1H-MRS imaging data demonstrated significant differences between suspected residual or recurrent tumor and contrast-enhancing radiation-induced necrosis. Regions of abnormally high choline (Cho) levels, consistent with viable tumor, were detected beyond the regions of contrast enhancement for all 12 gliomas. Changes in the serial 1H-MRS imaging data were observed, reflecting an altered metabolism following treatment. These changes included the significant reduction in Cho levels after therapy, indicating the transformation of tumor to necrotic tissue. For patients who demonstrated subsequent clinical progression, an increase in Cho levels was observed in regions that previously appeared either normal or necrotic. Several patients showed regional variations in response to brachytherapy as evaluated by 1H-MRS imaging. This study demonstrates the potential of noninvasive 3-D 1H-MRS imaging to discriminate between the formation of contrast-enhancing radiation necrosis and residual or recurrent tumor following brachytherapy. This modality may also allow better definition of tumor extent prior to brachytherapy by detecting the presence of abnormnal metabolite levels in nonenhancing regions of solid tumor.

Promising results have been obtained using brachytherapy in the treatment of brain tumors. Very low-dose rate brachytherapy (60-100 Gy given at 0.05-0.10 Gy/h) has been used for low-grade gliomas, resulting in 5- and 10-year survival probabilities of 85% and 83% for pilocytic astrocytomas and 61% and 51% for grade II astrocytomas. Only 2.6% of patients had symptomatic radiation necrosis. For faster-growing high-grade gliomas, temporary implants delivering about 60 Gy at 0.40-0.60 Gy/h are generally used. The largest series have reported median survival times of 12-13 months after brachytherapy for recurrent malignant gliomas and 18-19 months after diagnosis of primary glioblastomas treated with external beam radiotherapy and brachytherapy boost. A recent prospective, randomized trial demonstrated significantly improved survival for high-grade glioma patients who had brachytherapy boost. However, over 50% of patients who undergo brachytherapy for malignant gliomas require reoperation for tumor progression and/or radiation necrosis. Strategies are under development to improve local control without increasing radiation toxicity.

A retrospective review including long-term follow-up (4.6-12.0 years) was performed of all 28 pediatric patients who underwent high-activity 125I brachytherapy at the University of California, San Francisco, for primary or recurrent brain tumors from 1980 until 1991. There were 4 glioblastomas, 11 high-grade nonglioblastoma multiforme (NGM) malignant gliomas, 10 contrast-enhancing low-grade NGM, 2 choroid plexus carcinomas, and 1 rhabdomyosarcoma. The 13 survivors included 7 of 8 patients with primary high-grade NGM, 2 of 3 patients with primary low-grade NGM, and 3 of 7 patients with recurrent low-grade NGM. Necrosis (with or without tumor) was identified in 17 of 22 reoperated patients. The mean Karnofsky performance status was 88 +/- 9 at the time of brachytherapy, 87 +/- 7 at 3 years, and 87 +/- 9 in 11 patients alive at 6-12 years. Brachytherapy is a useful modality for treating selected pediatric brain tumors, and although focal necrosis is a common sequela, it does not tend to have a major impact on the Karnofsky performance status, if the implant site is amenable to reoperation.

Purpose: To evaluate brachytherapy dose-response relationships in adults with glioblastoma undergoing temporary 125I implant boost after external beam radiotherapy., Methods and Materials: Since June 1987, orthogonal radiographs using a fiducial marker box have been used to verify brain implant source positions and generate dose-volume histograms at the University of California, San Francisco. For adults who underwent brachytherapy boost for glioblastoma from June 1987 through December 1992, tumor volumes were reoutlined to ensure consistency and dose-volume histograms were recalculated. Univariate and multivariate analysis of various patient and treatment parameters were performed evaluating for influence of dose on freedom from local failure (FFLF) and actuarial survival., Results: Of 102 implant boosts, 5 were excluded because computer plans were unavailable. For the remaining 97 patients, analyses with adjustment for known prognostic factors (age, KPS, extent of initial surgical resection) and prognostic factors identified on univariate testing (adjuvant chemotherapy) showed that higher minimum brachytherapy tumor dose was strongly associated with improved FFLF (p = 0.001). A quadratic relationship was found between total biological effective dose and survival, with a trend toward optimal survival probability at 47 Gy minimum brachytherapy tumor dose (corresponding to about 65 Gy to 95% of the tumor volume); survival decreased with lower or higher doses. Two patients expired and one requires hospice care because of brain necrosis after brachytherapy doses > 63 Gy to 95% of the tumor volume with 60 Gy to > 18 cm3 of normal brain., Conclusion: Although higher minimum tumor dose was strongly associated with better local control, a brachytherapy boost dose > 50-60 Gy may result in life-threatening necrosis. We recommend careful conformation of the prescription isodose line to the contrast enhancing tumor volume, delivery of a minimum brachytherapy boost dose of 45-50 Gy in conjunction with conventional external beam radiotherapy, and reoperation for symptomatic necrosis.

Purpose: Various measures of the rate of tumor cell proliferation have been found to predict survival in patients with intracerebral gliomas. We correlated the bromodeoxyuridine labeling index (BrdUrd LI) with the response to radiation therapy, survival, and known prognostic factors in a series of patients with glioblastoma multiforme (GM) to test its utility as a prognostic factor., Methods and Materials: The BrdUrd LI was determined in 200 newly diagnosed intracranial GMs. Age and sex were known for all patients. The response to radiation therapy was determined in 116 patients by comparing neuroimaging studies obtained before and after external beam radiation therapy. Survival was analyzed in 64 patients who were treated according to two consecutive prospective clinical protocols., Results: The median BrdUrd LI was 6.5% (mean, 7.2%; range, 1.1-25.4%). The BrdUrd LI did not correlate significantly with age, sex, radiation response, or survival. Age and Karnofsky performance score were independent prognostic factors in our cohort., Conclusion: The proliferative rate as measured by BrdUrd LI was not a prognostic factor in our GM cohort. The BrdUrd LI did not correlate significantly with known prognostic factors in GM. There was no significant relationship between BrdUrd LI and radiation response.

The determine the value of radiographically assessed response to radiation therapy as a predictor of survival in patients with glioblastoma multiforme (GBM), the authors studied a cohort of 301 patients who were initially treated according to uniform clinical protocols. All patients had newly diagnosed supratentorial GBM and underwent the maximum safe resection followed by external- beam radiation treatment (60 Gy in standard daily fractions or 70.4 Gy in twice-daily fractions of 160 cGy). The radiation response and survival rates were assessable in 222 patients. The extent of resection and the immediate response to radiation therapy were highly correlated with survival, both in a univariate analysis and after correction for age and Karnofsky performance scale (KPS) score in a multivariate Cox model (p< 0.001 for radiation response and p=0.04 for extent of resection). A subgroup analysis suggested that neuroimaging obtained within 3 days after surgery served as a better baseline for assessment of radiation response than images obtained later. Imaging obtained within 3 days after completion of a course of radiation therapy also provided valid radiation response scores. The impact of the radiographically assessed radiation response on survival time was comparable to that of age or KPS score. This information is easily obtained early in the course of the disease, may be of value for individual patients, and may also have implications for the design and analysis of trials of adjuvant therapy for GBM, including volume-dependent therapies such as radiosurgery or brachytherapy.

Purpose: To determine clinically the fetal dose from irradiation of brain tumors during pregnancy and to quantitate the components of fetal dose using phantom measurements., Methods and Materials: Two patients received radiotherapy during pregnancy for malignant brain tumors. Case 1 was treated with opposed lateral blocked 10 x 15 cm fields and case 2 with 6 x 6 cm bicoronal wedged arcs, using 6 MV photons. Fetal dose was measured clinically and confirmed with phantom measurements using thermoluminescent dosimeters (TLDs). Further phantom measurements quantitated the components of scattered dose., Results: For case 1, both clinical and phantom measurements estimated fetal dose to be 0.09% of the tumor dose, corresponding to a total fetal dose of 0.06 Gy for a tumor dose of 68.0 Gy. Phantom measurements estimated that internal scatter contributed 20% of the fetal dose, leakage 20%, collimator scatter 33%, and block scatter 27%. For case 2, clinical and phantom measurements estimated fetal dose to be 0.04% of the tumor dose, corresponding to a total fetal dose of 0.03 Gy for a tumor dose of 78.0 Gy. Leakage contributed 74% of the fetal dose, internal scatter 13%, collimator scatter 9%, and wedge scatter 4%., Conclusions: When indicated, brain tumors may be irradiated to high dose during pregnancy resulting in fetal exposure < 0.10 Gy, conferring an increased but acceptable risk of leukemia in the child, but no other deleterious effects to the fetus after the fourth week of gestation. For our particular field arrangements and linear accelerators, internal scatter contributed a small component of fetal dose compared to leakage and scatter from the collimators and blocks, and 18 MV photons resulted in a higher estimated fetal dose than 6 MV photons due to increased leakage and collimator scatter. These findings are not universal, but clinical and phantom TLD measurements estimate fetal dose accurately for energies < 10 MV and should be taken for each pregnant patient considered for treatment to confirm and document acceptable dose.

A retrospective review was undertaken to study the influence of age on the survival of patients undergoing brachytherapy boost for glioblastoma multiforme. From February 1981 through December 1992, 159 adults with primary glioblastoma multiforme underwent high-activity iodine-125 brain implant boost after external beam radiotherapy. There were 98 men and 61 women, ranging in age from 18 to 73 years (median, 52 yr). Karnofsky performance scores ranged from 70 to 100 (median, 90). Surgery before radiotherapy consisted of biopsy in 7% of patients, subtotal resection in 66%, and gross total resection in 27%. External beam radiotherapy doses ranged from 39.6 to 76.8 Gy, with 91% of patients receiving 59.4 to 61.2 Gy. Brachytherapy doses ranged from 35.7 to 66.5 Gy (median, 55.0 Gy) at 0.30 to 0.70 Gy per hour (median, 0.43 Gy/h). Reoperations were performed in 81 patients (51%). Information on quality of life was available for 13 of the 14 living 3-year survivors; 10 patients were steroid independent, and mean Karnofsky performance scores had decreased from 92 at the time of brachytherapy to 75 at the last follow-up. Univariate and multivariate analyses showed that age was the most important parameter influencing survival (P < 0.0005). The nine patients 18 to 29.9 years old had a 3-year survival probability of 78 +/- 14% (median survival was not yet reached at the time of this report), with a follow-up of 145 to 511 weeks in living patients (median, 322 wk).(ABSTRACT TRUNCATED AT 250 WORDS)

Purpose: To study patterns of recurrence in patients with focal primary glioblastoma treated on Northern California Oncology Group protocol 6G-82-2 including surgery, focal external beam radiotherapy (59.4-60 Gy) with oral hydroxyurea followed by temporary brain implant with high-activity iodine-125 sources (50 Gy), and six cycles of chemotherapy with procarbazine, lomustine, and vincristine., Methods and Materials: Serial brain imaging scans were available for review in 25 of 34 patients with glioblastoma who underwent brain implant boost. Of 381 scans performed between the date of diagnosis and the date of death or last follow-up, 362 (95%) were re-reviewed. Disease progression was scored as local (within 2 cm of the implant site), separate within the brain parenchyma (> or = 2 cm from the implant site), subependymal, or systemic. Both initial and subsequent failures were scored., Results: Three patients are 5-year survivors, without evidence of disease, at 267, 292, and 308 weeks. Of the 22 initial sites of failure, 17 (77%) were local, three (14%) were separate brain lesions (one of which was due in retrospect to multicentric disease at diagnosis), one (5%) subependymal, and one (5%) systemic. Five patients with local failure later had other sites of failure, including a separate brain lesion in 1, subependymal spread in 3, and both in 1. One patient with separate brain failure later had local progression and then subependymal spread., Conclusion: Although there was a significant risk of separate brain lesions or subependymal spread over time, local tumor progression was the predominant pattern of failure.

Between January 1982 and January 1990, 107 patients with unifocal, circumscribed malignant gliomas participated in a non-randomized trial testing brachytherapy in their initial treatment. Focal external irradiation (6000 cGy) was combined with an implant of high-activity iodine-125 (5000-6000 cGy) and six courses of procarbazine, lomustine, and vincristine. Of the 101 evaluable patients, 63 received implants. Of these, 29 had non-glioblastoma anaplastic gliomas, and 34 had glioblastoma multiforme. The other 38 did not receive implants, in most cases because radiation therapy failed to reduce the size of the tumor. The median survival was 165 weeks for all evaluable patients with non-glioblastoma anaplastic gliomas, 157 weeks for those with implants, 67 weeks for all evaluable glioblastoma patients, and 88 weeks for those with implants. Of the glioblastoma patients with implants, nine were alive after 2 years, and three were alive after 3 years. In each of the groups, nearly half the patients underwent reoperation for clinical deterioration, increasing steroid dependency, and increasing mass effect at the implantation site after 46.1 weeks (median) for glioblastoma multiforme and 41.3 weeks for non-glioblastoma patients. Karnofsky Performance Scores showed only a small decline in performance after brachytherapy. Patients receiving implants for non-glioblastoma anaplastic gliomas had a mean Karnofsky Performance Score of 91% (range 90-100%) after 1 month and 78% (range 60-100%) 30 months after brachytherapy. Those treated for glioblastoma multiforme had a mean Karnofsky Performance Score of 86% (range 60-100%) at 1 month and 75% (range 60-100%) at 24 months. The quality of life of treated patients appears to be satisfactory. On the basis of comparisons with previous studies, we conclude that a brachytherapy "boost" after external irradiation may be valuable for some patients with glioblastoma multiforme but not for those with non-glioblastoma anaplastic gliomas.