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.
