Rationale.Glioblastoma (GBM) is the most common malignant primary tumor of the central nervous
system characterized by an extremely severe prognosis with a median survival of 14-16
months from diagnosis. Patients affected by high-grade gliomas are treated with a
combination of radiotherapy and temozolomide chemotherapy. To date, the efficacy of the
treatment is assessed through MRI which shows evidence of early radiological progression
in up to 50% of all patients. Importantly, signs of tumor progression on MRI images may
actually represent pseudoprogression in up to 64% of cases meaning that within 6 months
from the end of the radiation treatment 20-30% of patients show increased contrast
enhancement that resolves on subsequent MRI scans without changes in the treatment.
Pseudoprogression is a phenomenon likely related to inflammation and disruption of the
blood-brain barrier (BBB) caused by radiation and by the concurrent temozolomide
treatment. Being a self-resolving consequence of the therapy rather than a sign of tumor
growth, mistaking pseudoprogression for real progression leads to premature
discontinuation of therapy and inappropriate evaluation of progression free survival and
response rate in clinical trials impairing clinical practice.
Therefore, the differentiation of pseudoprogression from true progression is both a
challenge in everyday clinical activity and a relevant problem in clinical trials and
research.
A major limitation to the development and assessment of efficacy of current and new
therapies in the setting of brain tumors, both at preclinical and clinical levels,
however, is the lack of reliable trial endpoints.
A combination of advanced imaging methods, MRI and PET, with innovative techniques
investigating cancer-specific biology will allow a holistic characterization of the tumor
from multiple aspects crucial to enable a personalized diagnostic and therapeutical
approach.
Objective.The main goal of the project is the development and validation of imaging markers, MRI
and PET, plasma biomarkers, and/or cell markers that could support clinicians and
researchers in differentiating pseudoprogression from true tumor progression in routine
clinical activities and clinical trials in patients affected by GBM.
Main trial endpoints.The primary endpoint of the study is the elaboration of predictive models (evaluation of
specificity and sensitivity) using imaging advanced biomarkers, PET and MRI, biological
serum markers, and cancer cell derived makers to differentiate tumor pseudoprogression or
real progression in patients affected by GBM who underwent therapeutical protocol as per
treating physicians' indications (Stupp or hypofractionated RT).
Secondary trial endpoints.We aim to establish an in vivo murine model of pseudoprogression by orthotopic
transplantation of GSCs derived from thirty-five patient subjected to subsequent
treatment with irradiation and temozolomide administration.
Trial design.This is a pilot prospective interventional clinical trial using a novel 18F-GE-180 PET
radio-metabolic marker (AxMP) and MRI with advanced sequences with no modification of
standard of care treatment and additional diagnostic procedures that do not pose more
than minimal additional risk or burden to the subjects compared to normal clinical
practice. The trial will enroll 75 patients in 42 months and will be concluded in 60
months.
Trial population.The trial will prospectively enroll 75 patients affected by isocitrate dehydrogenase gene
(IDH)-wild type Glioblastoma, with an age above 18 years old , who will undergo standard
of care treatment.
Interventions.Before surgery and starting the standard treatment with RT and chemotherapy, all subjects
will undergo baseline MRI and 18F-GE-180 PET imaging, and blood withdrawal for evaluation
of plasma biomarkers of inflammation, circulating microvesicles, and RNA. MRI exams will
then be performed as per standard practice of care every 3 months and in case of clinical
deterioration suggesting possible disease recurrence/progression. A second PET-scan along
with plasma sample collection will be performed only in case of MRI evidence of either
suspected tumor progression or pseudoprogression. In case of MRI evidence of an increase
in tumor size (either suspected true tumor progression or pseudoprogression), as for
standard of care, the Institutional Multidisciplinary Brain Tumor Board (composed of
neurosurgeons, neuro-oncologists, neuroradiologists, radiotherapists) will discuss each
patient for determining clinical indication and feasibility of second surgery. In those
patients in whom second surgery is not indicated, a stereotactic biopsy will be
considered if feasible, safe, and clinically useful. If a stereotactic biopsy is not
feasible and safe, a 3-month follow-up will be planned before a change in treatment. When
available, pathology will be considered as the gold standard for differentiation
pseudoprogression from true tumor progression. In all other subjects, follow-up and
overall survival data will be evaluated for this differentiation. In all the subjects,
overall survival data will be also recorded for statistical analyses.
Cancer Stem Cells /CSC) will be collected form 35 patients and Hematopoietic Stem Cells
(HSC) from 10 patients for the creation of a vitro and in vivo murine model.
Ethical considerations relating to the clinical trial including the expected benefit to
the individual subject or group of patients represented by the trial subjects as well as
the nature and extent of burden and risks This trial will be conducted in compliance with
the protocol, the current version of the Declaration of Helsinki and International
Conference on Harmonization Good Clinical Practice guideline as well as international and
national legal and regulatory requirements.
All study participants will receive the standards of care for GBM. The additional
diagnostic procedures (PET scan with a novel tracer and high resolution 3 Tesla scanner
MRI) do not entail specific risks for the patient. At every time point (at least before
surgery, before RT and in case of pseudoprogression) additional blood samples for the
determinations of markers of inflammation and the isolation of circulating microvesicles
and RNA will be collected from the patients. Glioblastoma stem cells will be isolated
from the tumoral mass excised during glioblastoma surgery in 35 patients; hematopoietic
stem cells will be obtained from 10 consenting patients at the time of surgery by
aspiration of 30-40ml of bone marrow from the iliac crests, as per standard clinical
practice. Since the biopsy will be performed under general anesthesia, the patient should
not experience discomfort.
There are no expected benefits for the individual patient, but the study results might
provide important advances for the treatment of future patients.
