Safety Evaluation of a Combination of Brain Radiation Therapy and Bevacizumab (Avastin®) for Treatment of Brain Metastasis
Brain metastasis remain a common complication of many solid tumors, occurring from 10 to 20%
of patients with cancer, and the incidence may arise up to 20-40% in autopsy series.
Despite the treatment, the patient outcome is poor and brain metastasis become a major cause
of death from cancer.
Some recent studies showed an increase incidence of brain metastasis; several explanations
- The increased efficacy of brain imaging in screening of brain metastasis.
- The relative longer life expectancy of cancer patients in correlation with more
efficient therapies (new chemotherapy drugs, targeted therapies) for visceral and bone
metastasis, but without effect on the risk of brain metastasis (sanctuary effect),
Therapeutic management of brain metastasis: standards of care and improvement strategies
For patients with a poor survival hope, the treatment is limited to best supportive care
with a palliative intent. At the opposite, a specific treatment of brain metastasis must be
proposed when a real benefit may be expected.
Surgery or radiosurgery are indicated for limited brain involvement (1 to 3 metastasis).
In case of multiple localisations, whole brain radiation therapy (WBRT) is the most common
approach; however this treatment is realized with a palliative intent: control of
neurological symptoms and brain oedema.
In the literature, an objective response rate of 50-60 % is expected from WBRT, but the
majority of these patients will relapse and died from brain metastasis, with a median
survival time of 4 to 6 months.
Considering these poor results, it seems crucial to develop some innovative strategies, in
order to improve the survival hope for these patients.
Different concomitant approaches were tested in association with WBRT (cytotoxics such as
temozolomide, radio-sensitizers such as efaproxiral), and more recently combination of
radiation therapy with therapy targeting different signalling pathway were developed, for
example with lapatinib for HER2 pathway. Targeted therapies acting on neoangiogenesis seem
also may be considered as an interesting axis of research.
Rationale utilisation of angiogenesis inhibitors for treatment of brain metastasis
Neo-angiogenesis plays an important role in the growth of brain metastasis, acting on
different mechanisms such as tumor neo-angiogenesis (by development of new blood vessels),
co-option with existing blood vessels and increased vascular permeability. Therefore,
angiogenesis inhibitors, particularly agents targeting VEGF/VEGFR pathway, could be
interesting in the treatment of brain metastasis.
In pre-clinical models, VEGF is the best characterized mediator of angiogenesis, and its
role was pointed in the development of brain metastasis: increased transmigration of tumor
cells through the blood-brain barrier by a VEGF-dependent disrupting effect, anti-apoptotic
effect of VEGF by a paracrine action.
This data suggest a therapeutic effect of VEGF targeting agents on brain metastasis and a
decrease of brain metastasis development has been observed in some anti-VEGF anti-sens
Moreover, VEGF involves vascular permeability and this mechanism is important in the
development of peri-tumoral oedema.
Anti-angiogenic treatments are divided in two groups: on one hand, angiogenesis inhibitors
(acting by normalization of the existing tumor vascularisation and through a decreased
formation of new blood vessels) and on the other hand, vascular disrupting agents (which can
destroy pathologic vessels).
For brain tumors, most of studies were focused on the role of angiogenesis inhibitors. Of
special interest, anti-VEGF therapies, particularly the bevacizumab, were tested in clinical
setting. Bevacizumab, a monoclonal recombinant antibody targeting VEGF, prevents the
fixation of VEGF to VEGF receptors 1 and 2 on the endothelial cells, with a neutralizing
effect on VEGF action.
In clinic, recent studies showed a significant benefit of bevacizumab (Avastin®) in the
treatment of primary brain tumors, as shown by Vredenburgh et al. for patients with
recurrent gliomas; these data confirm a synergic effect with chemotherapy. Similarly, a
potential synergic action in a combined approach with radiation therapy seems to be an
interesting therapeutic way.
Rationale for combining angiogenesis inhibitors with radiation therapy
In the tumor, the pathologic neo-angiogenesis reduces the diffusion of oxygen, and
consequently promotes hypoxia. Hypoxia is one of the most causes of radio-resistance.
Ionizing radiations induce transient hypoxia in the central area of the tumor, increasing
the production of VEGF and consequently the neo-angiogenesis. This "vicious circle" allows
the development of optimal conditions for radio-resistance.
The normalization of pathologic vessels induced by angiogenesis inhibitors leads to a
decrease of hypoxia and thus enhance the radio-sensitivity of tumor cells and endothelial
In clinical setting, some studies were published about treatments combining radiation
therapy and angiogenic inhibitors. The main study was conducted for rectal carcinoma (9),
showing a safety profile of a combined scheme of bevacizumab and capecitabine in association
with pre-operative pelvic irradiation. Efficacy data are encouraging (downstaging for 9 /11
patients, histological regression for 5 patients). Similar conclusions may be drawn from
another study performed in patients with unresectable pancreatic carcinoma treated with a
radio-chemotherapy including bevacizumab, leading to an objective response for 9 patients
(20 %), 4 of them were operable at the end of radio-chemotherapy.
Interestingly, this combined approach seems interesting for brain tumors, as shown by a
recent published trial conducted by Narayana in first-line treatment of gliomas. This phase
2 study combined temozolomide chemotherapy with bevacizumab administration for a dose of 10
m/kg at D14 and D28 during the course of radiotherapy (total dose of 59,40 Gy delivered to
the tumor volume). An promising response rate was observed: 7% of complete response and 93%
of partial response, the 1-year progression-free survival was 59,3%. The authors confirm the
feasibility of this combined approach (13/15 patients completed their treatment). Three
grade 3-4 haematological toxicities and 4 non-haematological toxicities (thrombo-embolism
and HTA) are related. None intracerebral hemorrhage or death related to the treatment was
These results indicate a possible way of innovative strategies in the therapeutic management
of brain metastasis, by association of bevacizumab and whole brain radiation therapy.
Furthermore, bevacizumab is now indicated for several advanced and/or metastatic cancer but
its administration remains theorically contra-indicated for patients with brain metastasis,
due to the fear of potential cerebral hemorrhage. However, this risk remains low, as shown
by several studies.
Safety data were recorded with glioblastomas are reassuring, however, it is essential to
determine the optimal dose level of bevacizumab when combined with irradiation of the entire
brain at a dose of 30 Gy Thus for the phase 1 pilot study that we plan to carry, it is
important to test several dose levels of bevacizumab in combination with irradiation of the
brain: a precaution we have decided to use a conventional fractionation of 15 Gy in 2
fractions three weeks. Secondarily, given the good tolerability of this modality in
combination with three levels of dose of bevacizumab used, we propose to continue the phase
1 according to the scheme commonly used in palliative situation (30 Gy in 10 fractions and 2
weeks) in combination with Avastin at a dose of 15 mg / kg, at which a maximum limiting
toxicity has been observed.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
The Maximal Tolerated dose (MTD)
The primary objective is to determine the Maximal Tolerated Dose (MTD) of the combination of bevacizumab and whole brain radiation therapy for patients with brain metastases
The MTD will be evaluated 6 weeks after the first administration ob bevacizumab
Christelle LEVY, MD
Centre François Baclesse
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)