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Purpose: Despite standard of care (SOC) established by Stupp, glioblastoma remains a uniformly poor prognosis. We evaluated IGV-001, which combines autologous glioblastoma tumor cells and an antisense oligonucleotide against IGF type 1 receptor (IMV-001), in newly diagnosed glioblastoma., Patients and Methods: This open-label protocol was approved by the Institutional Review Board at Thomas Jefferson University. Tumor cells collected during resection were treated ex vivo with IMV-001, encapsulated in biodiffusion chambers with additional IMV-001, irradiated, then implanted in abdominal acceptor sites. Patients were randomized to four exposure levels, and SOC was initiated 4-6 weeks later. On the basis of clinical improvements, randomization was halted after patient 23, and subsequent patients received only the highest exposure. Safety and tumor progression were primary and secondary objectives, respectively. Time-to-event outcomes were compared with the SOC arms of published studies., Results: Thirty-three patients were enrolled, and median follow-up was 3.1 years. Six patients had adverse events (grade ≤3) possibly related to IGV-001. Median progression-free survival (PFS) was 9.8 months in the intent-to-treat population (vs. SOC, 6.5 months; P = 0.0003). In IGV-001-treated patients who met Stupp-eligible criteria, PFS was 11.6 months overall ( n = 22; P = 0.001) and 17.1 months at the highest exposure ( n = 10; P = 0.0025). The greatest overall survival was observed in Stupp-eligible patients receiving the highest exposure (median, 38.2 months; P = 0.044). Stupp-eligible patients with methylated O 6 -methylguanine-DNA methyltransferase promoter ( n = 10) demonstrated median PFS of 38.4 months ( P = 0.0008). Evidence of immune activation was noted., Conclusions: IGV-001 was well tolerated, PFS compared favorably with SOC, and evidence suggested an immune-mediated mechanism (ClinicalTrials.gov: NCT02507583)., (©2021 American Association for Cancer Research.)

Background: Brain metastases occur in up to 40% of all patients with systemic cancer. We aimed to assess whether stereotactic radiosurgery provided any therapeutic benefit in a randomised multi-institutional trial directed by the Radiation Therapy Oncology Group (RTOG)., Methods: Patients with one to three newly diagnosed brain metastases were randomly allocated either whole brain radiation therapy (WBRT) or WBRT followed by stereotactic radiosurgery boost. Patients were stratified by number of metastases and status of extracranial disease. Primary outcome was survival; secondary outcomes were tumour response and local rates, overall intracranial recurrence rates, cause of death, and performance measurements., Findings: From January, 1996, to June, 2001, we enrolled 333 patients from 55 participating RTOG institutions--167 were assigned WBRT and stereotactic radiosurgery and 164 were allocated WBRT alone. Univariate analysis showed that there was a survival advantage in the WBRT and stereotactic radiosurgery group for patients with a single brain metastasis (median survival time 6.5 vs 4.9 months, p=0.0393). Patients in the stereotactic surgery group were more likely to have a stable or improved Karnofsky Performance Status (KPS) score at 6 months' follow-up than were patients allocated WBRT alone (43% vs 27%, respectively; p=0.03). By multivariate analysis, survival improved in patients with an RPA class 1 (p<0.0001) or a favourable histological status (p=0.0121)., Interpretation: WBRT and stereotactic boost treatment improved functional autonomy (KPS) for all patients and survival for patients with a single unresectable brain metastasis. WBRT and stereotactic radiosurgery should, therefore, be standard treatment for patients with a single unresectable brain metastasis and considered for patients with two or three brain metastases.

Purpose: A multi-institutional trial was conducted by the Radiation Therapy Oncology Group (RTOG) to test the feasibility of performing a test battery consisting of five neurocognitive measures and a quality-of-life instrument in patients with brain metastases., Methods and Materials: The major eligibility requirements included histologic proof of a primary malignancy, measurable single or multiple brain metastases, Zubrod performance status of 0-1, neurologic function status of 0-2, and "certification" for administration of neurocognitive assessments. This certification process required either attendance at an RTOG neurocognitive assessment training workshop or review of an instructional video, followed by submission of an audiotape of mock/simulated test sessions for central review. The test battery included the following measures: the Mini-Mental Status Examination, Hopkins Verbal Learning Test, Verbal Fluency/Controlled Word Association Test, Ruff 2 and 7 test, Trailmaking Test, and Profile of Mood States-Short Form. The primary objective of this trial was to establish whether patients were able to complete this test battery. Compliance was defined as successful completion of a test measure. The test battery was to be administered just before, at completion of, and 1 month after whole brain radiotherapy to 37.5 Gy at 2.5 Gy/fraction once daily. Fifty-nine patients were enrolled in the trial., Results: The patient characteristics included 32% > or =65 years; 44% with Zubrod performance status of 0; and 81% with multiple brain metastases. The overall compliance rate for administration and completion of the five neurocognitive measures and a quality-of-life instrument before treatment, at treatment completion, and 1 month after treatment was > or =95%, > or =84%, and > or =70%. The most common causes of noncompliance were patient-related factors (e.g., performance status or inability to understand test instructions) and not institutional error., Conclusion: Neurocognitive evaluation of patients with brain metastases in a multi-institutional and cooperative group setting is feasible using the test battery and certification process used in this study. This battery and certification process will be incorporated into future RTOG brain tumor trials.

Radiation Therapy Oncology Group (RTOG) trial 94-02 is designed to compare the effectiveness of radiation therapy alone with radiation therapy plus procarbazine, lomustine, and vincristine (PCV) chemotherapy in patients with anaplastic oligodendrogliomas and mixed oligoastrocytomas. This prospectively collected, randomly treated, prospectively followed cohort is the ideal set of patients to validate the observation that anaplastic oligodendrogliomas with 1p and 19q deletions have a prolonged survival and a better response to chemotherapy. For patients entered on RTOG 94-02, fresh blood specimens, as well as slides and paraffin blocks, have been obtained (with informed consent) on enrollment. Peripheral blood leukocytes (buffy coats) have been frozen and stored and Epstein-Barr-virus-immortalized lymphoblastoid lines have been prepared from the blood specimens. In this report, the authors describe a pilot 1p/19q deletion analysis of 26 tumors from RTOG trial 94-02. In this analysis, it is shown that 1p/19q deletion analysis by fluorescence in situ hybridization is feasible on blocks collected from this trial. Also demonstrated is that the incidence of 1p and 19q deletions in this pilot series of anaplastic oligodendrogliomas and mixed oligoastrocytomas is similar to that reported in previous studies. When the clinical follow-up on this prospective trial is mature and the deletion studies have been completed, the authors should be able to determine whether 1p and 19q deletions predict a prolonged survival and/or responsiveness to PCV chemotherapy plus radiation in patients with anaplastic oligodendrogliomas and mixed oligoastrocytomas.

Purpose: To examine the effect of treatment using Bromodeoxyuridine (BrdU) during radiation therapy on malignant glioma patient survival by comparing historical survival data from several large clinical trials., Methods: A retrospective analysis of patient data from Radiation Therapy Oncology Group (RTOG) trials 74-01, 79-18, and 83-02 and the Northern California Oncology Group (NCOG) study 6G-82-1 was conducted. Patient data was supplied by both groups, and analyzed by the RTOG. Pretreatment characteristics including age, extent of surgery, Karnofsky Performance Status (KPS), and histopathology were collected; the only treatment variable evaluated was the use of BrdU during radiation therapy. Radiation dose, dose-fractionation schedule, use of chemotherapy, and/or type of chemotherapy was not controlled for in the analyses. Univariate and multivariate analyses were conducted to examine the potential treatment effect of BrdU on patient survival., Results: Data from 334 patients treated with BrdU on NCOG 6G-82-1 and 1743 patients treated without BrdU on 3 RTOG studies was received. Patients were excluded from the review if confirmation of eligibility could not be obtained, if the patient was ineligible for the study they entered, if central pathology review was not done, or if radiotherapy data was not available. Patients treated according to the RTOG studies had to start radiotherapy within 4 weeks of surgery; no such restriction existed for the NCOG studies. To ensure comparability between the studies, patients from the NCOG studies who began treatment longer than 40 days from surgery were also excluded. The final data set included 296 cases from the NCOG studies (89%) and 1478 cases from the RTOG studies (85%). For patients with glioblastoma multiforme (GBM) the median survival was 9.8 months in the RTOG studies and 13.0 months in the NCOG trial (p < 0.0001). For patients with AA the median survival was 35.1 months for the RTOG studies and 42.8 months in the NCOG trial (p = 0.126). Univariate results showed consistent results favoring BrdU among patients over 30 years of age, across the extent of surgery, and for GBM patients. A proportional hazards regression model that included treatment, histopathology, KPS, age, and extent of surgery demonstrated that treatment with BrdU was included in the best model only for the GBM group of patients (risk ratio 0.83)., Conclusions: Because of the heterogeneity of the treatment groups, including potentially important differences in pathology reviewers assessment of nonglioblastoma cases, differences in radiation dose and schedules, and chemotherapy during or after radiation, these analyses cannot provide the definitive answer as to whether BrdU given during radiation therapy improves survival in patients with malignant glioma. There does appear to be a favorable treatment effect seen in patients with GBM, with a lesser effect in patients with AA.

The goal of therapeutic intervention in oncology patients is to prolong survival without compromising its quality. Definition and measurement of quality are quite difficult. This article discusses the statistical techniques for quantifying quality survival that have been used in brain tumor patients. These techniques assume either that all patients have equivalent baseline quality of life when both disease-related symptoms and toxicities are absent, or that the length of time with a predetermined level of impairment is equivalent to death. These models do not fit the heterogeneous symptoms experienced by patients with malignant brain tumors. We propose a model that incorporates the baseline states with transitions to different levels of severity that indicate improvement and/or declines in physical and cognitive functioning of brain tumor patients. The length of time spent in each state is observed and weighted by using predetermined utilities. The weighted time spent in each state is aggregated over all states into a quality-time of survival metric (QTIME). This QTIME model was applied to a previously published, randomized clinical trial of different radiation doses in malignant brain tumor patients.

Purpose: Seven percent of patients with high grade gliomas enrolled in RTOG 83-02 had mixed astrocytoma/oligodenroglial elements on central pathology review. It has often been assumed that the most aggressive histologic component of a tumor determines biologic behavior; however in this trial, the survival of patients who had mixed glioblastomas/oligodenrogliomas was significantly longer than that of patients with pure glioblastomas (GBM). We therefore evaluated the effect of an oligodendroglial component on the survival of patients who had anaplastic astrocytomas (AAF) treated in the same trial., Methods and Materials: One hundred nine patients who had AAF and 24 patients with mixed AAF/oligodendrogliomas (AAF/OL) were enrolled in a Phase I/II trial of randomized dose-escalation hyperfractioned radiotherapy plus BCNU. AAF/OL patients were older and more likely to have had more aggressive surgery than AAF patients. Other pretreatment characteristics were balanced between groups, as was assigned treatment., Results: The median survival time for AAF was 3.0 years versus 7.3 years for AAF/OL (p = 0.019). In a multivariate analysis, adjusting for extent of surgical resection and age, an oligodendroglial component was an independent prognostic factor for survival., Conclusion: The results support the concept that AAFs with an oligodendroglial component have a better prognosis than pure AAF tumors, similar to the effect seen among patients with glioblastoma multiforme tumors. This better survival outcome should be taken into consideration in the design and stratification of future trials. Additionally, in contrast to patients with GBMs, patients who have AAF/OL have the potential for prolonged survival; therefore, late sequelae of treatment (both radiation and chemotherapy) must be weighed more heavily in the benefits to risks analysis.

We investigated the possible influence of race on the survival of patients with malignant gliomas enrolled in three consecutive trials of the Radiation Therapy Oncology Group (RTOG) retrospectively using the group's statistical database. There were no statistical differences between the survival rates for black patients with glioblastoma multiforme (GBM) and those for the white patients. The limited influence of therapy on this disease may be responsible in part for this result.

Purpose: To determine if the addition of bromodeoxyuridine (BrdUrd) to radiotherapy prolongs survival when compared to radiotherapy alone in patients with brain metastases., Methods and Materials: Seventy-two patients with brain metastases were randomized to 37.5 Gy in 15 fractions of 2.5 Gy or to the same dose with BrdUrd 0.8 g/m2 per day for 4 days of each of 3 weeks. Drug treatment was begun on Thursday or Friday before the first week of radiotherapy. Patients had a Karnofsky performance score of at least 70, a neurological function classification of 1 or 2, and any primary tumor except central nervous system (CNS), leukemia, or lymphoma. The primary was absent, controlled, or under active radiotherapy. Patients were free of other metastases. They were stratified by primary site (breast, lung or other), number of metastases (single or multiple) and age (< 60 vs. > 60)., Results: There was no significant difference between the two treatment arms (p = 0.904). The study was open from October 1989 to March 1993 and accrued 72 patients. Only one patient in the RT only arm remains alive. The two treatment arms were balanced with respect to all stratification variables. Toxicity due to radiotherapy was similar in both arms. BrdUrd caused significant Grade 4 and 5 hematologic and skin toxicity in five patients. Two patients died due to hematologic toxicity and one from a Stevens-Johnson type skin reaction. Phenytoin played a role in the skin reactions and ranitidine was associated with the hematologic deaths. Ranitidine was eliminated, BrdUrd was discontinued after any hematologic toxicity, and no further Grade 4 or 5 toxicities were seen. The median survival was 6.12 months in the radiotherapy group and 4.3 in the BrdUrd group (p = 0.904). Patients with solitary brain metastases had significantly better survival (p = 0.031)., Conclusions: BrdUrd did not enhance the efficacy of the radiotherapy regimen tested, in spite of the fact that brain metastases have shown high labeling indices. The toxicity of this schedule of BrdUrd administration was apparently increased by ranitidine and phenytoin.

Background: A Phase I/II randomized dose-seeking trial was performed to document the severity, time course, and significance of white matter changes seen on serial imaging scans (magnetic resonance imaging, computed tomography) associated with bis-chlorethyl nitrosourea (BCNU) and hyperfractionated cranial irradiation., Methods: Long term survivors (> or = 18 months) were identified from a prospective randomized dose-escalation Phase I/II trial designed to evaluate twice-daily radiotherapy for supratentorial high grade malignant gliomas. All scans were reviewed by a neuroradiologist who had no information about the prescribed dose and fractionation. In the trial, patients were assigned to receive 64.8 Gy, 72.0 Gy, 76.8 Gy, or 81.4 Gy (all fractionated as 1.2 Gy twice a day [bid]), or 48.0 Gy or 54.4 Gy (both in 1.6-Gy bid fractions). Bis-chlorethyl nitrosourea was administered every 8 weeks for 1 year. Of 747 randomized patients, 177 had analyzable scans. The scans reviewed were those acquired preoperatively, immediately postoperatively, 3, 6, 12, and 18 months after radiotherapy. Radiographic endpoints included no white matter change (Grade 0), minimal patchy white matter foci (Grade 1), start of confluence of white matter disease (Grade 2), large confluent areas (Grade 3), confluence with cortical/subcortical involvement (Grade 4), leukoencephalopathy (Grade 5), and possible necrosis (Grade 6) according to the classification of F. Fazekas et al. The effects were scored relative to the baseline preoperative scans. The dose pairs of 48 Gy and 54.4 Gy, 64.8 Gy and 72 Gy, and 76.8 Gy and 81.4 Gy were grouped together for analysis (low, intermediate, and high dose, respectively). Toxicity was analyzed in three ways: Grade 2 or worse, Grade 3 or worse, and Grade 6., Results: Grade 2 or worse changes were observed in 26.6, 27.6, and 40.4% of patients in the low, intermediate, and high dose groups, respectively. Grade 3 or worse changes were observed in 8.3, 20.0, and 36.5% of patients in the low, intermediate, and high dose groups, respectively. Grade 6 changes were observed in 1.6, 4.6, and 19.2% of patients in the low, intermediate, and high dose groups, respectively. No statistically significant differences were observed among treatment groups when toxicity was evaluated as Grade 2 or worse. For toxicity of Grade 3 or worse, an chi-square test revealed P values of 0.04 (low vs. intermediate dose), 0.09 (intermediate vs. high dose), and 0.0005 (low vs. high dose). With the endpoint of possible necrosis (Grade 6), P values were 0.21 (low vs. intermediate dose), 0.05 (intermediate vs. high dose), and 0.003 (low vs. high dose). The median time to radiographic appearance of an effect (15 months) was not influenced by total dose or fraction size., Conclusions: A well described toxicity scale for white matter injury was applied successfully to patients with malignant glioma treated with definitive irradiation. Severe white matter changes continued to increase significantly as the total dose of hyperfractionated cranial irradiation was escalated. The time to onset of the white matter abnormalities appeared to be independent of dose. An ongoing Radiation Therapy Oncology Group study will allow correlation of white matter injury with prospective neuropsychometric testing.

Background: Despite notable technical advances in therapy for malignant gliomas during the past decade, improved patient survival has not been clearly documented, suggesting that pretreatment prognostic factors influence outcome more than minor modifications in therapy. Age, performance status, and tumor histopathology have been identified as the pretreatment variables most predictive of survival outcome. However, an analysis of the association of survival with both pretreatment characteristics and treatment-related variables is necessary to assure reliable evaluation of new approaches for treatment of malignant glioma., Purpose: This study of malignant glioma patients used a non-parametric statistical technique to examine the associations of both pretreatment patient and tumor characteristics and treatment-related variables with survival duration. This technique was used to identify subgroups with survival rates sufficiently different to create improvements in the design and stratification of clinical trials., Methods: We used a recursive partitioning technique to analyze survival in 1578 patients entered in three Radiation Therapy Oncology Group malignant glioma trials from 1974 to 1989 that used several radiation therapy (RT) regimens with and without chemotherapy or a radiation sensitizer. This approach creates a regression tree according to prognostic variables that classifies patients into homogeneous subsets by survival. Twenty-six pretreatment characteristics and six treatment-related variables were analyzed., Results: The years). Patients younger than 50 years old were categorized by histology (astrocytomas with anaplastic or atypical foci [AAF] versus glioblastoma multiforme [GBM]) and subsequently by normal or abnormal mental status for AAF patients and by performance status for those with GBM. For patients aged 50 years or older, performance status was the most important variable, with normal or abnormal mental status creating the only significant split in the poorer performance status group. Treatment-related variables produced a subgroup showing significant differences only for better performance status GBM patients over age 50 (by extent of surgery and RT dose). Median survival times were 4.7-58.6 months for the 12 subgroups resulting from this analysis, which ranged in size from 32 to 256 patients., Conclusions: This approach permits examination of the interaction between prognostic variables not possible with other forms of multivariate analysis., Implications: The recursive partitioning technique can be employed to refine the stratification and design of malignant glioma trials.

Background: Although there have been occasional reports of improved response with greater doses of irradiation for unresected brain metastases, dose escalation has not been systematically studied in a cohort of patients with solitary brain metastasis. The current study examines this group of patients to evaluate dose escalation using accelerated hyperfractionated radiation therapy (XRT) with regard to survival, patterns of failure, and toxicity., Method: Radiation Therapy Oncology Group (RTOG) 85-28, a Phase I/II randomized trial of accelerated hyperfractionated XRT for patients with unresected supratentorial brain metastases, enrolled 153 patients with solitary brain metastasis. Whole brain dose was 32 Gray (Gy) administered in 1.6 Gy fractions twice a day with an interfraction interval of 4-8 hours. Boost dose was escalated to total doses of 48.0, 54.4, 64.0, and 70.4 Gy., Results: Acute and late toxicities were acceptable. The median survival time and 1-year survival rates were 4.9 months and 20% at 48 Gy; 5.4 months and 33% at 54.4 Gy; 7.2 months and 28% at 64 Gy; and 8.2 months and 37% at 70.4 Gy, respectively. Comparison of the upper three dose treatment arms to the 48 Gy treatment arm revealed a superior survival time with doses of 54.4 Gy and greater (P = 0.05). Improvement in neurologic function appeared to increase with dose escalation, with 25% of patients experiencing improvement at doses of 48 Gy, 38% at 54.4 Gy, 50% at 64 Gy, and 63% at 70.4 Gy (P = not significant)., Conclusion: A radiation dose response for survival time appears to exist with the use of accelerated hyperfractionated XRT for patients with unresected solitary brain metastasis.

103 patients with the diagnosis of AAF were identified from the RT/BCNU arms of 3 RTOG malignant glioma trials. Pre-treatment tumor size was less than 5 cm for 48% and greater than or equal to 5 cm for 52%, and tumor sites were frontal lobe in 55%, temporal in 25%, and parietal in 16%. Surgery consisted of biopsy for 30%, partial resection for 56%, and total resection for 14%. Extent of surgery correlated with age, with 81% of patients less than 40 undergoing partial/total resection vs. 60% of those over 40 (P = 0.019). The median survival time (MST) of patients undergoing partial/total resection was 49 mo., vs. 18 mo. for those biopsied only (P = 0.002). Patients with frontal location had longer MST than those with non-frontal lesions (MST: 49 vs. 25 mo., P = 0.047), while no survival difference was apparent by univariate analysis of tumor size. Multivariate analysis demonstrated that only younger age, frontal location, and smaller tumor size correlated significantly with extended survival. Extent of surgery was not predictive. The close correlation between young age and extensive surgery obscures the survival advantage for greater surgery seen with univariate analysis. Smaller tumor size and frontal location favorably influence outcome even when adjusted by age.