Therapy In Neuro-oncology Research Articles

P17.89 * EFFECTS OF GLIOBLASTOMA FIRST-LINE TRIALS ON TIME DELAY TO INITIATION OF TREATMENT, SIGNS OF EARLY TUMOR PROGRESSION AND PROGRESSION-FREE SURVIVAL

Randomized clinical trials based on molecular markers such as MGMT promoter methylation are pivotal to further develop the field of medical therapies in neuro-oncology. However, shipping of material and central review of histology and molecular markers significantly delay treatment start in patients with glioblastoma. To evaluate a treatment disadvantage for patients in clinical trials, we performed a retrospective analysis of 3 prospective Phase II and III clinical trials for the treatment of patients with high-grade gliomas in first-line therapy. In this study we examined 23 patients we enrolled during the last 3 years into controlled prospective multicenter European glioblastoma treatment trials for the incidence of an early MRI progression. Pre- and post-surgery MRI, baseline MRI, follow-up MRI, date of operation, date of progression and overall survival were collected for 23 patients, 22 of them with glioblastoma and 1 with gliosarcoma. Early MRI progression was evaluated based on the RANO criteria by 2 independent neuroradiologists and stratified into no, unlikely, possible and definite progression, based on new contrast enhancement distant from the resection site, nodular and eccentric contrast enhancement at the resection site or a combination of both. Progression-free survival (PFS) was defined as the time from resection to treatment failure during first-line therapy, and overall survival (OS) as time from resection to death. We observed a profound delay between resection and treatment start if patients were treated within trials with central histology and molecular marker evaluation with a mean of 30.2 days between surgery and baseline examination. At baseline MRI, 56% of patients had definite signs of early progression, whereas 26% had no signs of early progression. The 6 patients with no signs of early progression had a mean time delay between surgery and study inclusion of 28.3 days, which was not significantly different from the 30.5 days in the group of 13 patients with definite signs of early progression (p = 0.210; Mann-Whitney test). However, regarding the PFS of both groups we found a significant difference in favor of the group with “no” early progression signs (“no” signs of early progression: PFS = 188 days, 95% CI (120-255) and “definite” signs of early progression: PFS = 403 days, 95% CI (281-526); p = 0.018; log rank test). In this small pilot dataset, we cannot support a correlation between time delay to treatment and signs of early tumor progression. However, we observe a statistically significant correlation between signs of early tumor progression at baseline MRI and PFS. We plan to expand this analysis to support the hypothesis that a delayed treatment initiation leads to early tumor progression, which negatively influences progression-free survival.

EORTC topics in neurooncology: The long path from a focus on neurological complications of cancer towards molecularly defined trials and therapies in neurooncology

Over the past decade a series of trials of the EORTC Brain Tumor Group (BTG) has substantially influenced and shaped the standard-of-care of primary brain tumors. All these trials were coupled with biological research that has allowed for better understanding of the biology of these tumors. In glioblastoma, EORTC trial 26981/22981 conducted jointly with the National Cancer Institute of Canada Clinical Trials Group showed superiority of concomitant radiochemotherapy with temozolomide over radiotherapy alone. It also identified the first predictive marker for benefit from alkylating agent chemotherapy in glioblastoma, the methylation of the O6-methyl-guanyl-methly-transferase (MGMT) gene promoter. In another large randomized trial, EORTC 26951, adjuvant chemotherapy in anaplastic oligodendroglial tumors was investigated. Despite an improvement in progression-free survival this did not translate into a survival benefit. The third example of a landmark trial is the EORTC 22845 trial. This trial led by the EORTC Radiation Oncology Group forms the basis for an expectative approach to patients with low-grade glioma, as early radiotherapy indeed prolongs time to tumor progression but with no benefit in overall survival. This trial is the key reference in deciding at what time in their disease adult patients with low-grade glioma should be irradiated.Future initiatives will continue to focus on the conduct of controlled trials, rational academic drug development as well as systematic evaluation of tumor tissue including biomarker development for personalized therapy. Important lessons learned in neurooncology are to dare to ask real questions rather than merely rapidly testing new compounds, and the value of well designed trials, including the presence of controls, central pathology review, strict radiology protocols and biobanking. Structurally, the EORTC BTG has evolved into a multidisciplinary group with strong transatlantic alliances. It has contributed to the maturation of neurooncology within the oncological sciences.

Neurooncology clinical trial design for targeted therapies: Lessons learned from the North American Brain Tumor Consortium

The North American Brain Tumor Consortium (NABTC) is a multi-institutional consortium with the primary objective of evaluating novel therapeutic strategies through early phase clinical trials. The NABTC has made substantial changes to the design and methodology of its trials since its inception in 1994. These changes reflect developments in technology, new types of therapies, and advances in our understanding of tumor biology and biological markers. We identify the challenges of early clinical assessment of therapeutic agents by reviewing the clinical trial effort of the NABTC and the evolution of the protocol template used to design trials. To better prioritize effort and allocation of patient resources and funding, we propose an integrated clinical trial design for the early assessment of efficacy of targeted therapies in neurooncology. This design would mandate tissue acquisition prior to therapeutic intervention with the drug, allowing prospective evaluation of its effects. It would also include a combined phase 0/I pharmacokinetic study to determine the safety and biologically optimal dose of the agent and to verify successful modulation of the target prior to initiating a larger, phase II efficacy study.

Cell therapies in neuro-oncology

During their growth, malignant gliomas interact with the immune system and are able to escape immune reactions. Attempts to instruct the immune system to develop anti-glioma reactions have been partly unsuccessful. Recent advances in the molecular and cellular biology of dendritic cells (DC), however, may increase the chances of preparing effective "vaccines" against these tumours. We show that vaccination with DC pulsed with a tumour lysate considerably increases survival in mice bearing intracranial glioblastomas. These results support the development of DC-based clinical trials for patients with glioblastomas that do not respond to standard therapies.

Neurosurgical Delivery of Chemotherapeutics, Targeted Toxins, Genetic and Viral Therapies in Neuro-Oncology

Local delivery of biologic agents, such as gene and viruses, has been tested preclinically with encouraging success, and in some instances clinical trials have also been performed. In addition, the positive pressure infusion of various therapeutic agents is undergoing human testing and approval has already been granted for routine clinical use of biodegradable implants that diffuse a chemotherapeutic agent into peritumoral regions. Safety in glioma patients has been shown, but anticancer efficacy needs additional refinements in the technologies employed. In this review, we will describe these modalities and provide a perspective on needed improvements that should render them more successful.