Kevin O. Lillehei

OBJECT: The Glioma Outcomes Project represents a contemporary analysis of the management of malignant (Grade III and Grade IV/GBM) gliomas in North America. This observational database was used to evaluate the influence of resection, as opposed to biopsy, on patient outcome as measured by the length of survival. Attempts were made to reduce the impact of selection bias by repeating the data analysis after omitting patients with major negative prognostic factors. METHODS: Outcome data from 788 patients accrued from multiple sites over a 4-year period (1997-2001) were analyzed with the primary outcome measure being length of survival. Of these, 565 patients with recent diagnoses formed the basis of the present analysis. Patients were systematically followed up until death or up to 24 months after enrollment in the study, and survival data were correlated with the histopathological grade and location of the tumor, the extent of surgery, the patient's performance status, and demographic factors. The median length of survival was 40.9 weeks for patients with recently diagnosed GBMs. The true median length of survival for patients with Grade III gliomas was not reached, although there was a 58% survival rate at 104 weeks. In multivariate analysis, resection rather than biopsy (p < 0.0001), age 60 years or younger (p < 0.0001), and a Karnofsky Performance Scale (KPS) score of 70 or greater (p = 0.0004) were associated with a prolonged survival time for patients with Grade III or IV gliomas. The prognostic value of resection compared with biopsy was maintained (p < 0.0001), even after eliminating patients considered to be "poor risk" (those with age > 60 years, KPS score < 70, or presence of multifocal tumors), who may have been overrepresented in the biopsy group. Survival "tails" at 24 months were 58% for Grade III gliomas and 11% for GBMs. CONCLUSIONS: These data provide Class II evidence to support tumor grade, patient's age, and patient's functional status as prognostic factors for survival in individuals with recently diagnosed malignant gliomas. Resection (compared with biopsy) is also a strong prognostic factor; however, no quantitative attempt was made to assess the true extent of the resection.

BACKGROUND: -L) to standard therapy for newly diagnosed glioblastoma. METHODS: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). RESULTS: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. CONCLUSIONS: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.

Importance: Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed. Objective: To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma. Design, Setting, and Participants: This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021. Interventions: The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies. Main Outcomes and Measures: The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials. Results: A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03). Conclusions and Relevance: In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone. Trial Registration: ClinicalTrials.gov Identifier: NCT00045968.

OBJECT: In many new clinical trials of patients with malignant gliomas surgical intervention is incorporated as an integral part of tumor-directed interstitial therapies such as gene therapy, biodegradable wafer placement, and immunotherapy. Assessment of toxicity is a major component of evaluating these novel therapeutic interventions, but this must be done in light of known complication rates of craniotomy for tumor resection. Factors predicting neurological outcome would also be helpful for patient selection for surgically based clinical trials. METHODS: The Glioma Outcome Project is a prospectively compiled database containing information on 788 patients with malignant gliomas that captured clinical practice patterns and patient outcomes. Patients in this series who underwent their first or second craniotomy were analyzed separately for presenting symptoms, tumor and patient characteristics, and perioperative complications. Preoperative and intraoperative factors possibly related to neurological outcome were evaluated. There were 408 patients who underwent first craniotomies (C1 group) and 91 patients who underwent second ones (C2 group). Both groups had similar patient and tumor characteristics except for their median age (55 years in the C1 group compared with 50 years in the C2 group; p = 0.006). Headache was more common at presentation in the C1 group, whereas papilledema and an altered level of consciousness were more common at presentation in patients undergoing second surgeries. Perioperative complications occurred in 24% of patients in the C1 group and 33% of patients in the C2 group (p = 0.1). Most patients were the same or better neurologically after surgery, but more patients in the C2 group (18%) displayed a worsened neurological status than those in the C1 group (8%; p = 0.007). The Karnofsky Performance Scale score and, in patients in the C2 group, tumor size were important neurological outcome predictors. Regional complications occurred at similar rates in both groups. Systemic infections occurred more frequently in the C2 group (4.4 compared with 0%; p < 0.0001) as did depression (20 compared with 11%; p = 0.02). The perioperative mortality rate was 1.5% for the C1 group and 2.2% for the C2 group (p = not significant). The median length of the hospital stay was 4 days in each group. CONCLUSIONS: Perioperative complications occur slightly more often following a second craniotomy for malignant glioma than after the first craniotomy. This should be considered when evaluating toxicities from intraoperative local therapies requiring craniotomy. Nevertheless, most patients are neurologically stable or improved after either their first or second craniotomy. This data set may serve as a benchmark for neurosurgeons and others in a discussion of operative risks in patients with malignant gliomas.