Germline polymorphisms in MGMT associated with temozolomide-related myelotoxicity risk in patients with glioblastoma treated on NRG Oncology/RTOG 0825.

Background: We sought to identify clinical and genetic predictors of temozolomide-related myelotoxicity among patients receiving therapy for glioblastoma. Methods: Patients (n = 591) receiving therapy on NRG Oncology/RTOG 0825 were included in the analysis. Cases were patients with severe myelotoxicity (grade 3 and higher leukopenia, neutropenia, and/or thrombocytopenia); controls were patients without such toxicity. A risk-prediction model was built and cross-validated by logistic regression using only clinical variables and extended using polymorphisms associated with myelotoxicity. Results: 23% of patients developed myelotoxicity (n = 134). This toxicity was first reported during the concurrent phase of therapy for 56 patients; 30 stopped treatment due to toxicity. Among those who continued therapy (n = 26), 11 experienced myelotoxicity again. The final multivariable clinical factor model included treatment arm, gender, and anticonvulsant status and had low prediction accuracy (area under the curve [AUC] = 0.672). The final extended risk prediction model including four polymorphisms in MGMT had better prediction (AUC = 0.827). Receiving combination chemotherapy (OR, 1.82; 95% CI, 1.02-3.27) and being female (OR, 4.45; 95% CI, 2.45-8.08) significantly increased myelotoxicity risk. For each additional minor allele in the polymorphisms, the risk increased by 64% (OR, 1.64; 95% CI, 1.43-1.89). Conclusions: Myelotoxicity during concurrent chemoradiation with temozolomide is an uncommon but serious event, often leading to treatment cessation. Successful prediction of toxicity may lead to more cost-effective individualized monitoring of at-risk subjects. The addition of genetic factors greatly enhanced our ability to predict toxicity among a group of similarly treated glioblastoma patients.

Independently validated sex-specific nomograms for predicting survival in patients with newly diagnosed glioblastoma: NRG Oncology RTOG 0525 and 0825.

BACKGROUND/PURPOSE: Glioblastoma (GBM) is the most common primary malignant brain tumor. Sex has been shown to be an important prognostic factor for GBM. The purpose of this study was to develop and independently validate sex-specific nomograms for estimation of individualized GBM survival probabilities using data from 2 independent NRG Oncology clinical trials. METHODS: This analysis included information on 752 (NRG/RTOG 0525) and 599 (NRG/RTOG 0825) patients with newly diagnosed GBM. The Cox proportional hazard models by sex were developed using NRG/RTOG 0525 and significant variables were identified using a backward selection procedure. The final selected models by sex were then independently validated using NRG/RTOG 0825. RESULTS: Final nomograms were built by sex. Age at diagnosis, KPS, MGMT promoter methylation and location of tumor were common significant predictors of survival for both sexes. For both sexes, tumors in the frontal lobes had significantly better survival than tumors of multiple sites. Extent of resection, and use of corticosteroids were significant predictors of survival for males. CONCLUSIONS: A sex specific nomogram that assesses individualized survival probabilities (6-, 12- and 24-months) for patients with GBM could be more useful than estimation of overall survival as there are factors that differ between males and females. A user friendly online application can be found here- https://npatilshinyappcalculator.shinyapps.io/SexDifferencesInGBM/ .

Neurocognitive, symptom, and health-related quality of life outcomes of a randomized trial of bevacizumab for newly diagnosed glioblastoma (NRG/RTOG 0825).

BACKGROUND: Results of NRG Oncology RTOG 0825 reported adding bevacizumab to standard chemoradiation did not significantly improve survival endpoints and resulted in greater decline in neurocognitive function (NCF) and patient-reported outcomes (PRO) over time in bevacizumab-treated patients. The present report provides additional results of patient-centered outcomes over time and their prognostic association with survival endpoints. METHODS: NCF tests, MD Anderson Symptom Inventory - Brain Tumor Module (MDASI-BT), and European Organization for Research and Treatment of Cancer (EORTC) quality of life (QOL) questionnaire with brain cancer module (QLQ-C30/BN20) were completed in a subset of progression-free patients at baseline and longitudinally. The prognostic value of baseline and early changes in NCF and PROs and differences between treatments from baseline to follow-up assessments were evaluated. RESULTS: A total of 508 randomized patients participated. Baseline/early changes in NCF and PROs were prognostic for OS and PFS. No between-arm differences in time to deterioration were found. At week 6, patients treated with bevacizumab evidenced greater improvement on NCF tests of executive function and the MDASI-BT Cognitive Function scale, but simultaneously reported greater decline on the EORTC Cognitive Function Scale. At later time points (weeks 22, 34, and 46), patients treated with bevacizumab had greater worsening on NCF tests as well as PRO measures of cognitive, communication, social function, motor symptoms, general symptoms, and interference. CONCLUSION: The collection of patient-centered clinical outcome assessments in this phase III trial revealed greater deterioration in NCF, symptoms, and QOL in patients treated with bevacizumab. Baseline and early change in NCF and PROs were prognostic for survival endpoints.

NRG/RTOG 1122: A phase 2, double-blinded, placebo-controlled study of bevacizumab with and without trebananib in patients with recurrent glioblastoma or gliosarcoma.

BACKGROUND: Targeting vascular endothelial growth factor (VEGF) alone does not improve overall survival (OS) in recurrent glioblastoma (rGBM). The angiopoiein (Ang)-TIE2 system may play a role in tumor survival under VEGF inhibition. We conducted a phase 2, double-blinded, placebo-controlled trial of bevacizumab plus trebananib (a novel Fc fusion protein that sequesters Ang1/Ang2) over bevacizumab alone in rGBM. METHODS: Patients ≥18 years of age with a Karnofsky performance status ≥70 and GBM or variants in first or second relapse were randomized to bevacizumab 10 mg/kg every 2 weeks plus trebananib 15 mg/kg every week or bevacizumab plus placebo. The primary endpoint was 6-month progression-free survival (PFS). RESULTS: After an initial 6-patient lead-in cohort confirmed the safety of combining bevacizumab and trebananib, 115 eligible patients were randomized to the control (n = 58) or experimental treatment (n = 57). In the control arm, 6-month PFS was 41.1%, median survival time was 11.5 months (95% CI, 8.4-14.2 months), median PFS was 4.8 months (95% CI, 3.8-7.1 months), and radiographic response (RR) was 5.9%. In the experimental arm, 6-month PFS was 22.6%, median survival time was 7.5 months (95% CI, 6.8-10.1 months), median PFS was 4.2 months (95% CI, 3.7-5.6 months), and RR was 4.2%. The rate of severe toxicities was not significantly different between arms. CONCLUSION: The combination of bevacizumab and trebananib was well tolerated but did not significantly improve 6-month PFS rate, PFS, or OS for patients with rGBM over bevacizumab alone. The shorter PFS in the experimental arm with a hazard ratio of 1.51 (P = .04) suggests that the addition of trebananib to bevacizumab is detrimental.

The association of health-related quality of life and cognitive function in patients receiving memantine for the prevention of cognitive dysfunction during whole-brain radiotherapy.

BACKGROUND: This study evaluated the association between health-related quality of life (HRQOL) and cognition in patients receiving memantine for prevention of cognitive dysfunction during whole-brain radiotherapy (WBRT). METHODS: Adult patients with brain metastases received WBRT and were randomized to receive placebo or memantine, 20 mg per day, within 3 days of initiating radiotherapy, for 24 weeks. The Functional Assessment of Cancer Therapy-Brain module (FACT-Br) and Medical Outcomes Scale-Cognitive Functioning Scale (MOS-C) were completed in coordination with serial standardized tests of cognitive function. RESULTS: Of the 508 eligible patients, 442 (87%) consented to participate in the HRQOL portion and contributed to baseline analyses. Evaluable patients at 24 weeks (n = 246) included surviving patients completing FACT-Br, MOS-C, and objective cognitive assessments (n = 146, 59%) and patients alive at time of missed assessment (n = 100, 41%). Baseline cognitive function correlated significantly with FACT-Br and MOS-C self-reports. All domains of objective cognitive function showed declines over time. Neither FACT-Br nor MOS-C differed between the treatment arms. Emotional and functional well-being subscales of the FACT improved over time while the remainder of the FACT-Br domains remained stable. MOS-C scores declined over time. CONCLUSION: Baseline cognitive function correlated significantly with FACT-Br and MOS-C scores. No by-arm differences in HRQOL were observed despite differences in objective cognitive function. Patient attrition and poor testing compliance remain significant problems in studies of cognitive function of brain metastases patients and further effort is needed to improve compliance with testing and sensitivity of patient-reported measures.

Influence of Residual Disease Following Surgical Resection in Newly Diagnosed Glioblastoma on Clinical, Neurocognitive, and Patient Reported Outcomes.

BACKGROUND: The influence of subtotal resection (STR) on neurocognitive function (NCF), quality of life, and symptom burden in glioblastoma is unknown. If bevacizumab preferentially benefits patients with STR is unknown. OBJECTIVE: To examine these uncertainties. METHODS: NCF and patient reported outcomes (PRO) were prospectively collected in NRG Oncology RTOG 0525 and 0825. Changes in NCF and PRO measures from baseline to prespecified times were examined by Wilcoxon test, and mixed effects longitudinal modeling, to assess differences between patients who received STR vs gross-total resection. Changes were also compared among STR patients on 0825 receiving placebo vs bevacizumab to assess for a preferential therapeutic effect. Overall survival between STR and gross-total resection patients was compared using the Kaplan-Meier method. RESULTS: A total of 427 patients were eligible with STR present in 37%. At baseline, patients with STR had worse NCF, worse MD Anderson Symptom Inventory Brain Tumor Neurological Factor ratings (P = .004), and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (P = .002). Longitudinal multivariate analysis associated STR with worse NCF (Hopkins Verbal Learning Test-Revised Delayed Recognition [P = .048], Trail Making Test Part A [P = .035], and Controlled Oral Word Association [P = .049]). One hundred eighty-three STR patients from 0825 were analyzed (89 bevacizumab, 94 placebo); bevacizumab failed to demonstrate improvement in select NCF or PRO measures. CONCLUSION: STR patients had worse NCF and PROs before therapy. During adjuvant therapy, STR patients had worse objective NCF, despite accounting for tumor location. STR did not result in a detriment to OS. The addition of bevacizumab did not preferentially improve PRO or NCF outcomes in STR patients.

Short delay in initiation of radiotherapy for patients with glioblastoma-effect of concurrent chemotherapy: a secondary analysis from the NRG Oncology/Radiation Therapy Oncology Group database.

Background: We previously reported the unexpected finding of significantly improved survival for newly diagnosed glioblastoma in patients when radiation therapy (RT) was initiated later (>4 wk post-op) compared with earlier (≤2 wk post-op). In that analysis, data were analyzed from 2855 patients from 16 NRG Oncology/Radiotherapy Oncology Group (RTOG) trials conducted prior to the era of concurrent temozolomide (TMZ) with RT. We now report on 1395 newly diagnosed glioblastomas from 2 studies, treated with RT and concurrent TMZ followed by adjuvant TMZ. Our hypothesis was that concurrent TMZ has a synergistic/radiosensitizing mechanism, making RT timing less significant. Methods: Data from patients treated with TMZ-based chemoradiation from NRG Oncology/RTOG 0525 and 0825 were analyzed. An analysis comparable to our prior study was performed to determine whether there was still an impact on survival by delaying RT. Overall survival (OS) was investigated using the Kaplan-Meier method and Cox proportional hazards model. Early progression (during time of diagnosis to 30 days after RT completion) was analyzed using the chi-square test. Results: Given the small number of patients who started RT early following surgery, comparisons were made between >4 and ≤4 weeks delay of radiation from time of operation. There was no statistically significant difference in OS (hazard ratio = 0.93; P = 0.29; 95% CI: 0.80-1.07) after adjusting for known prognostic factors (recursive partitioning analysis and O6-methylguanine-DNA methyltransferase methylation status). Similarly, the rate of early progression did not differ significantly (P = 0.63). Conclusions: We did not observe a significant prognostic influence of delaying radiation when given concurrently with TMZ for newly diagnosed glioblastoma. The effects of early (1-3 wk post-op) or late (>5 wk) initiation of radiation tested in our prior study could not be replicated.

A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblastoma: results of NRG Oncology RTOG 0913.

Background: This phase II study was designed to determine the efficacy of the mammalian target of rapamycin (mTOR) inhibitor everolimus administered daily with conventional radiation therapy and chemotherapy in patients with newly diagnosed glioblastoma. Methods: Patients were randomized to radiation therapy with concurrent and adjuvant temozolomide with or without daily everolimus (10 mg). The primary endpoint was progression-free survival (PFS) and the secondary endpoints were overall survival (OS) and treatment-related toxicities. Results: A total of 171 patients were randomized and deemed eligible for this study. Patients randomized to receive everolimus experienced a significant increase in both grade 4 toxicities, including lymphopenia and thrombocytopenia, and treatment-related deaths. There was no significant difference in PFS between patients randomized to everolimus compared with control (median PFS time: 8.2 vs 10.2 mo, respectively; P = 0.79). OS for patients randomized to receive everolimus was inferior to that for control patients (median survival time: 16.5 vs 21.2 mo, respectively; P = 0.008). A similar trend was observed in both O6-methylguanine-DNA-methyltransferase promoter hypermethylated and unmethylated tumors. Conclusion: Combining everolimus with conventional chemoradiation leads to increased treatment-related toxicities and does not improve PFS in patients with newly diagnosed glioblastoma. Although the median survival time in patients receiving everolimus was comparable to contemporary studies, it was inferior to the control in this randomized study.

CogState computerized memory tests in patients with brain metastases: secondary endpoint results of NRG Oncology RTOG 0933.

Whole brain radiotherapy (WBRT) is associated with memory dysfunction. As part of NRG Oncology RTOG 0933, a phase II study of WBRT for brain metastases that conformally avoided the hippocampal stem cell compartment (HA-WBRT), memory was assessed pre- and post-HA-WBRT using both traditional and computerized memory tests. We examined whether the computerized tests yielded similar findings and might serve as possible alternatives for assessment of memory in multi-institution clinical trials. Adult patients with brain metastases received HA-WBRT to 30 Gy in ten fractions and completed Hopkins Verbal Learning Test-Revised (HVLT-R), CogState International Shopping List Test (ISLT) and One Card Learning Test (OCLT), at baseline, 2 and 4 months. Tests' completion rates were 52-53 % at 2 months and 34-42 % at 4 months. All baseline correlations between HVLT-R and CogState tests were significant (p ≤ 0.003). At baseline, both CogState tests and one component of HVLT-R differentiated those who were alive at 6 months and those who had died (p ≤ 0.01). At 4 months, mean relative decline was 7.0 % for HVLT-R Delayed Recall and 18.0 % for ISLT Delayed Recall. OCLT showed an 8.0 % increase. A reliable change index found no significant changes from baseline to 2 and 4 months for ISLT Delayed Recall (z = -0.40, p = 0.34; z = -0.68, p = 0.25) or OCLT (z = 0.15, p = 0.56; z = 0.41, p = 0.66). Study findings support the possibility that hippocampal avoidance may be associated with preservation of memory test performance, and that these computerized tests also may be useful and valid memory assessments in multi-institution adult brain tumor trials.

Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial.

PURPOSE: Hippocampal neural stem-cell injury during whole-brain radiotherapy (WBRT) may play a role in memory decline. Intensity-modulated radiotherapy can be used to avoid conformally the hippocampal neural stem-cell compartment during WBRT (HA-WBRT). RTOG 0933 was a single-arm phase II study of HA-WBRT for brain metastases with prespecified comparison with a historical control of patients treated with WBRT without hippocampal avoidance. PATIENTS AND METHODS: Eligible adult patients with brain metastases received HA-WBRT to 30 Gy in 10 fractions. Standardized cognitive function and quality-of-life (QOL) assessments were performed at baseline and 2, 4, and 6 months. The primary end point was the Hopkins Verbal Learning Test-Revised Delayed Recall (HVLT-R DR) at 4 months. The historical control demonstrated a 30% mean relative decline in HVLT-R DR from baseline to 4 months. To detect a mean relative decline ≤ 15% in HVLT-R DR after HA-WBRT, 51 analyzable patients were required to ensure 80% statistical power with α = 0.05. RESULTS: Of 113 patients accrued from March 2011 through November 2012, 42 patients were analyzable at 4 months. Mean relative decline in HVLT-R DR from baseline to 4 months was 7.0% (95% CI, -4.7% to 18.7%), significantly lower in comparison with the historical control (P < .001). No decline in QOL scores was observed. Two grade 3 toxicities and no grade 4 to 5 toxicities were reported. Median survival was 6.8 months. CONCLUSION: Conformal avoidance of the hippocampus during WBRT is associated with preservation of memory and QOL as compared with historical series.

RTOG 0913: a phase 1 study of daily everolimus (RAD001) in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma.

PURPOSE: To determine the safety of the mammalian target of rapamycin inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients. METHODS AND MATERIALS: Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (75 mg/m(2) per day). Everolimus was escalated from 2.5 mg/d (dose level 1) to 5 mg/d (dose level 2) to 10 mg/d (dose level 3). Adjuvant temozolomide was delivered at 150 to 200 mg/m(2) on days 1 to 5, every 28 days, for up to 12 cycles, with concurrent everolimus at the previously established daily dose of 10 mg/d. Dose escalation continued if a dose level produced dose-limiting toxicities (DLTs) in fewer than 3 of the first 6 evaluable patients. RESULTS: Between October 28, 2010, and July 2, 2012, the Radiation Therapy Oncology Group 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria receiving the drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined maximum tolerated dose of 10 mg/d. Two of the first 6 eligible patients had a DLT at each dose level. DLTs included gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were grade 1 or 2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was 1 death reported, which was attributed to tumor progression. CONCLUSIONS: Daily oral everolimus (10 mg) combined with both concurrent radiation and temozolomide followed by adjuvant temozolomide is well tolerated, with an acceptable toxicity profile. A randomized phase 2 clinical trial with mandatory correlative biomarker analysis is currently under way, designed to both determine the efficacy of this regimen and identify molecular determinants of response.

Novalis intensity-modulated radiosurgery: methods for pretreatment planning.

OBJECTIVE: The Novalis stereotactic radiotherapy system (BrainLAB, Heimstetten, Germany) allows for precise treatment of cranial base tumors with single-fraction radiosurgery. In some cases, however, proximity of the optic nerve and chiasm is a concern. In these cases, intensity-modulated stereotactic radiosurgery (IMRS) can be used to limit the dose to these structures. IMRS planning can be labor intensive, which poses a problem when it is performed on the day of treatment. We describe our methods and results of preprocedure planning for IMRS for patients with lesions in the cavernous sinus or parasellar regions in whom the dose to the optic nerve or chiasm might exceed our acceptable tolerance dose (8 Gy). METHODS: Patients whose lesions were more than 4 mm from the optic nerve and chiasm on standard magnetic resonance imaging scans but who were questionable candidates for radiosurgery because of concerns of dose to the optic nerve or chiasm were considered for IMRS. Preprocedure imaging (computed tomography and magnetic resonance imaging) was fused and analyzed using the BrainLAB BrainScan 5.3 treatment planning system. Dynamic conformal arc plans for stereotactic radiosurgery and IMRS were evaluated. Doses to the planning target volume and optic apparatus were assessed by dose-volume histograms and conformality index calculated to characterize the quality of the different plans. When IMRS was used, the preplan allowed for a rapid recalculation on the treatment day, minimizing the time patients were in the head frame before treatment. RESULTS: We describe three patients with recurrent pituitary tumors and three with meningiomas. Doses were 1500 to 2000 cGy prescribed to the 80 to 96% isodose line delivered by eight to 22 fields. Tumor volumes ranged from 2.70 to 8.82 cm (mean, 5.7 cm). In five of the six patients, the dynamic conformal arc plan precluded delivery of therapeutic dose without exceeding optic nerve tolerance. On the basis of 95% coverage of target volume, maximum prescription doses of 7.7 to 20.64 Gy were possible with the dynamic conformal arc plans without exceeding 8 Gy to the optic apparatus. IMRS allowed maximum doses of 20 to 31 Gy using the same optic apparatus dose restriction. No complications have occurred, and all tumors have remained stable since treatment (mean follow-up period, 30 mo). CONCLUSION: We believe this pretreatment technique streamlines the process for IMRS, allowing for better patient comfort and efficient physician time use.

A comparison of the cell lines used in meningioma research.

BACKGROUND: Immortal cell lines and cell lines derived from operative specimens transplanted into animal models are used in meningioma research. We address 2 criticisms of the mouse xenograft flank tumor model: Why are tumor induction rates derived from operative specimens low and inconsistent? Are flank tumors meningiomas? METHODS: Meningioma cell cultures were processed for Giemsa-band karyotyping and flow cytometry. Mouse flank tumors induced subcutaneously were analyzed microscopically, immunohistochemically, and ultrastructurally. Giemsa-band studies identified meningiomas with simple karyotype (< or =1 chromosomal abnormality) or complex karyotype (multiple chromosomal abnormalities). RESULTS: Cell cultures with complex karyotypes (IOMM-Lee, CH-157 MN, 2 operative specimens) grew rapidly in vitro and induced tumors in 49 (98%) of 50 animals. Meningioma cell cultures with simple karyotypes grew slowly in vitro and showed small, nongrowing tumors in mouse flanks (10/10). Meningioma flank tumors were vimentin-positive with ultrastructural features consistent with meningiomas. Cell cultures with complex karyotypes grew faster in cell culture and consistently induced flank tumors, unlike meningiomas with simple karyotypes. CONCLUSIONS: Meningioma cell lines transplanted into flanks of nude mice exhibit microscopic, immunohistochemical, and ultrastructural features of meningiomas. The ease of monitoring tumor growth in the subcutaneous mouse flank model is its primary advantage, although we recognize an intracranial location is more biologically desirable.

The impact of involved field radiation therapy in the treatment of relapsed or refractory non-Hodgkin lymphoma with high-dose chemotherapy followed by hematopoietic progenitor cell transplant.

BACKGROUND: Patients with refractory/relapsed non-Hodgkin lymphoma (NHL) often receive high-dose chemotherapy (HDCT) followed by hematopoietic progenitor cell transplant (HPCT) as salvage therapy. We examined the role of involved field radiation therapy (IFRT) in this setting. METHODS: The records of 167 patients with refractory/relapsed NHL who underwent HDCT followed by HPCT between February 1990 and November 2003 were reviewed. Fifty-three patients received IFRT and 114 did not receive IFRT in the peritransplant period. RESULTS: Eighty patients were alive at the time of analysis with a median follow up for alive patients of 4.5 years in the no IFRT group and 4.2 years in the IFRT group (P = 0.53). Patients undergoing IFRT were more likely to have bulky (P = 0.02) and extranodal (P= 0.04) disease at initial diagnosis. There was no significant difference between the treatment groups regarding mortality in the first 100 days after HPCT (P = 0.31). Five-year overall survival rates were 46.7% for the no IFRT group and 40.0% for the IFRT group (P= 0.15). Disease-free survival was significantly worse for patients receiving IFRT (P = 0.02); however, when considering local control, the addition of IFRT resulted in a 5-year rate similar to that for patients who did not receive IFRT (68.6% vs. 72.0% respectively, P= 0.73). CONCLUSIONS: Although disease-free survival was inferior in patients who received IFRT, despite more adverse clinical features the use of IFRT resulted in similar rates of local control and overall survival compared with those who did not receive IFRT. The use of IFRT was not associated with an increase in the risk of acute mortality or late events.

Peritumoral edema after stereotactic radiosurgery for intracranial meningiomas and molecular factors that predict its development.

INTRODUCTION: Stereotactic radiosurgery (SRS) is an effective treatment for small and medium-sized meningiomas. Although uncommon, peritumoral edema can develop as a delayed complication after SRS. The purpose of the study was to evaluate the clinical and molecular risk factors for peritumoral edema after SRS for intracranial meningiomas. METHODS: We retrospectively reviewed the results from 18 patients with intracranial meningiomas who underwent SRS. Tissue was obtained from 14 of these patients who also underwent surgery (13 before SRS). Peritumoral edema, before and after SRS, was estimated using the edema index. Quantitative differences in molecular markers of angiogenesis (VEGF, VRGFr) and hypoxia (HIF-1, GLUT-1, and CA-IX) as well as proliferative indices between patients with and without an elevated edema index after SRS were evaluated. RESULTS: Of the 18 patients studied, symptomatic peritumoral edema developed in three after SRS. They were treated with steroids and one required surgical intervention. The mean time to edema onset was 5.5 months, with an average duration of 16 months. Sagittal sinus occlusion and high-grade histology appear to be more common in the edema group. VEGF and HIF-1 were found in tumors with higher edema index and the elevation of these proteins was correlated with peritumoral edema after SRS. Proliferative index was not predictive for peritumoral edema. CONCLUSION: Clinical characteristics and molecular markers may identify patients with meningiomas at risk of peritumoral edema after SRS. Judicious use of steroids or perhaps the use of stereotactic fractionated radiation should be considered in these high-risk patients.

The risk of secondary malignancies over 30 years after the treatment of non-Hodgkin lymphoma.

BACKGROUND: Survivors of non-Hodgkin lymphoma (NHL) are at increased risk for developing secondary malignancies. For the current study, the authors quantitated this risk in a group of NHL survivors over 30 years of follow-up. METHODS: Standardized incidence ratios (observed-to-expected [O/E] ratio) and absolute excess risk of secondary malignancies were assessed in 77,876 patients who were diagnosed with NHL between 1973 and 2001 from centers that participated in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. RESULTS: There were 5638 patients who developed secondary malignancies, significantly more than the endemic rate (O/E, 1.14; P < .001). Overall, irradiated patients had a similar risk of secondary malignancies compared with unirradiated patients (relative risk, 1.04; 95% confidence interval, 0.98-1.10; P = .21). Irradiated patients had excess risk for sarcomas, breast cancers, and mesothelioma compared with unirradiated survivors (P < .05). Patients age <25 years at the time of their NHL diagnosis had the highest relative increased risk (no radiation: O/E, 2.1; P < .05; radiation: O/E, 4.51; P < .05). Overall, no statistical difference was observed for secondary cancer incidence between females and males (O/E, 1.12 vs. 1.15, respectively). Female survivors of NHL were less likely to develop breast cancer than the general population (O/E, 0.85; P < .05), but women age <25 years at the time of their NHL diagnosis were more likely to develop breast cancer (no radiation: O/E, 2.1; P < .05; radiation: O/E, 4.51; P < .05). CONCLUSIONS: The overall risk of secondary malignancies was increased for NHL survivors and varied according to age at NHL diagnosis, gender, and treatment.

The impact of involved field radiation therapy for patients receiving high-dose chemotherapy followed by hematopoietic progenitor cell transplant for the treatment of relapsed or refractory Hodgkin disease.

OBJECTIVES: Patients with refractory/relapsed Hodgkin disease (HD) often receive high-dose chemotherapy (HDCT) followed by hematopoietic progenitor cell transplant (HPCT) as salvage therapy. This study sought to determine if involved field radiation therapy (IFRT) in this setting improves patient outcomes. METHODS: The records of 65 patients with refractory/relapsed HD who underwent HDCT followed by HPCT between September 1988 and October 2003 were retrospectively reviewed. Forty-four patients did not receive IFRT and 21 received IFRT. RESULTS: Thirty-eight patients were alive at the time of analysis with a median follow-up of 3.4 years in the no IFRT group and 1.8 years in the IFRT group (P = 0.38). IFRT patients were more likely to have bulky disease at initial diagnosis (P = 0.05). Progression-free survival (PFS) was similar in the 2 groups (P = 0.83). Twenty-two patients in the no IFRT group and 5 in the IFRT group have died (P = 0.06). Five-year overall survival rates were 55.6% for the no IFRT group and 73.3% for the IFRT group (P = 0.16). There was no significant difference between the treatment groups regarding mortality in the first 100 days after HPCT (P = 0.41), late events (P = 0.26), or failure in sites previously involved with disease (P = 0.76). CONCLUSIONS: Although the current study did not demonstrate an improvement in PFS with the addition of IFRT to HDCT and HPCT, there was a trend toward improved overall survival. The potential benefit of IFRT may be underestimated because of the heterogeneity of the treatment groups. The use of IFRT was not associated with an increase in the risk of acute mortality or late events.

Extraneural metastatic medulloblastoma in an adult.

Medulloblastoma is a rare malignancy in adults, accounting for approximately 1% of all primary brain tumors. Extraneural metastases have been reported in 10-30% of cases and most commonly involve bone; rarely lymph nodes, visceral organs and bone marrow may be involved with disease. We report here our experience with a 26 year-old woman with medulloblastoma treated with gross total resection followed by radiation therapy to her craniospinal axis. She subsequently developed widespread metastatic disease involving bone exclusive of the calvarium and spine for which multi-agent salvage chemotherapy was utilized with initial good clinical response. She later relapsed within the lymph nodes and soft tissues of the pelvis and eventually suffered a local recurrence within the posterior fossa. The treatment of medulloblastoma, particularly salvage therapy following disease recurrence, is reviewed.

Basic principles of radiobiology, radiotherapy, and radiosurgery.

This article reviews the basic principles of radiobiology and the application thereof to the treatment of metastatic spine tumors. The most important concepts of dose fractionation and the concept of biologically effective dose as well as spinal cord tolerance to single and multiple doses of radiotherapy are emphasized. Basic principles of treatment planning for radiotherapy and radiosurgery are outlined.

Time interval to the development of breast carcinoma after treatment for Hodgkin disease.

BACKGROUND: Women with Hodgkin disease (HD) who received mantle irradiation had an increased risk of developing breast carcinoma. The authors examined the influence of radiotherapy on the time interval to the development of breast carcinoma. METHODS: Using population, cancer incidence, and survival data from the Surveillance, Epidemiology, and End Results (SEER) registries, standardized incidence ratios (SIR) were calculated and Kaplan-Meier curves were constructed to estimate breast carcinoma-free survival in women with HD treated with and without radiotherapy. The log-rank test was utilized and multivariate proportional hazard regression analysis was performed. Multivariate analysis was also performed using the PHPH regression model. RESULTS: In 9 SEER registries, 8036 females were identified who were diagnosed with HD between 1973 and 1999. Of these women, 183 (2.3%) were subsequently diagnosed with breast carcinoma. The use of radiotherapy in the treatment of HD resulted in an increased risk of development of breast carcinoma (SIR = 1.90, P < 0.01). The log-rank test and proportional hazard regression model failed to detect a difference (P = 0.79) in breast carcinoma-free survival for women treated with and without radiotherapy. The PHPH regression model revealed that the use of radiotherapy had an adverse effect on long-term survival (relative risk [RR] = 1.84, P = 0.01), but was associated with a short-term survival advantage (RR = 0.45, P = 0.01). CONCLUSIONS: Use of the PHPH model indicated that the use of radiotherapy in the treatment of HD resulted in an increased long-term risk for the subsequent development of breast carcinoma, but conferred a short-term reduction.