BACKGROUND
- - Glioblastoma (GBM) is the most common and aggressive primary brain tumour in
adults.
The standard first-line treatment for these tumours features maximized surgery
followed by radiation with concomitant and adjuvant temozolomide. The overall survival
(OS) and progression-free survival (PFS) observed in the clinic with this paradigm are
only 14.6 and 6, 9 months respectively. One of the challenges in the treatment of this
neoplasm stems from the severe tumour heterogeneity which translates into unpredictable
treatment response. As a result, newly diagnosed tumours inevitably relapse after the
standard first-line treatment, which is called the Stupp protocol which combines
radiation therapy and oral temozolomide. When recurrence occurs, if the patient's
functional status is adequate, this will mandate other therapeutic strategies.
Interestingly, results obtained in most studies in this setting have been so marginal
that there is literally no recognized optimal second and third line of treatment.
Admittedly, the access to active therapies is greatly limited by the presence of the
blood-brain barrier (BBB), which severely reduces the chemotherapy entry to the CNS.
When one realizes the extensiveness of the vascular network supplying the brain, it
appears obvious that a global delivery strategy via this vascular network as a delivery
corridor is credible and legitimate. The importance of this vascular system has already
been detailed by Bradbury; the author claims that the entire network covers an area of 12
m2/g of cerebral parenchyma. To understand the extensiveness of the cerebral
vascularization in a more prosaic way, let us just consider that the brain receives about
20% of the total systemic circulation although it weighs less than 3% of the total body
weight.
The access to a patient's cerebral vascular network is technically easy and actually
repeatedly performed in the clinic on a regular basis. Via a simple puncture to access
the femoral artery, a catheter can be introduced and navigated intraarterially to reach
one of the four major cerebral arteries. Once in the target vessel, a therapeutic agent
can be administered via the catheter, that is later withdrawn at the conclusion of the
procedure. The CIAC allows the construct of a regional chemotherapeutic distribution
paradigm within the area irrigated by the targeted vessel.
An increase in the local plasma peak concentration of the drug yields a significantly
improved AUC (concentration of drug according to the time) through the first pass effect.
This consequently translates in an increased local exposure of the target tissue to the
therapeutic agent. Interestingly, as our lab as shown, it is also accompanied by a
decreased systemic drug distribution, hence reducing systemic toxicity and potential side
effects. Consequently, the therapeutic concentration at the targeted tumour cells is
increased by a 3.5 to 5-fold factor. This procedure is performed in the angiographic
suite under local anesthesia and typically lasts around 45 minutes.
The IA procedure is a very safe procedure. Indeed, this procedure has been used at our
institution for over 15 years using various chemotherapeutic agents and thus have precise
statistics on the risks and complications. Indeed, 722 different patients have been
treated adding up to 3600 procedures and have compiled the following events. During the
MRI that followed the IA infusion, 66 complications were identified (1.84%), 27 of which
were associated to symptoms (0.75%). During the infusion, 39 episodes of seizures
occurred (1.08%), all of which were successfully controlled with anti-seizure medication.
Moreover, a significant reduction in white, red or platelet blood cell count occurred in
52 patients during the treatment phase (7.2%). This study will investigate the efficacy
of using combined chemotherapeutic agents described above. Our team currently uses
intraarterial (IA) infusion to alleviate the effects of the BBB. This delivery strategy
was shown to be well tolerated, triggered very few discomforts and side effects, and
significantly improved survival. So much so, that it is nowadays considered a standard of
care for relapsing tumours in our institution.
Like cisplatin, carboplatin is a molecule made of a platinum atom surrounded in a plane
by two ammonia groups and two other ligands in the cis position. Unlike the chloride
atoms found in cisplatin, the ligands in carboplatin are esther functional groups that
form a ring structure. As such, carboplatin is more stable, causes less vomiting and is
less neurotoxic, less ototoxic and less nephrotoxic. Carboplatin's exact mechanism of
action remains unclear. However, it is well known that carboplatin is activated inside
the cell into reactive platinum species. These reactive complexes react with DNA bases to
create inter- and intrastrand crosslinks which prevent cell division by hindering DNA
synthesis.
At our institution, carboplatin is the primary chemotherapeutic agent for IA infusions
and yields positive tumour responses in 70% of patients for a median PFS of 5 months.
Although interesting, there is obviously room for improvement in the care of these
patients. Hence the current proposal.
For patients in which carboplatin fails, other chemotherapeutics are chosen arbitrarily
from a list of agents available for IA infusion. As such, our team has successfully
treated relapsing GBM patients with IA delivery of methotrexate, melphalan, etoposide
phosphate or Caelyx (liposomal doxorubicin). At the heart of the present study,
carboplatin, which will be combined with either one of two agents found to be ideally
suited in this setting: Caelyx (liposomal doxorubicin) or etoposide phosphate.
Doxorubicin is an anthracycline, an antineoplastic antibiotic developed from Streptomyces
peucetius subsp. Cassius. It is a very potent antitumour agent and is considered one of
the most active antineoplastic drugs developed to date. Its effect is produced via
different mechanisms: DNA binding and cross-linking, interference with DNA strand
separation, inhibition of RNA polymerase, inhibition of topoisomerase II, formation of
free radicals and membrane peroxidation have all been suggested.
In vitro studies in malignant glial cell lines have demonstrated that doxorubicin induces
a halt in cell growth within 24 hours, and results in apoptosis within 48 hours. It has
been identified as one of the most potent chemotherapeutic drugs against malignant glioma
cell lines in vitro. However, in vivo, the use of doxorubicin is limited by its inability
to cross the BBB.
Doxorubicin is rapidly distributed in the body tissues, and binds to plasma protein and
cell membranes. The clinical application of this agent is unfortunately limited by its
dose-related side effects such as cardiotoxicity and myleotoxicity.
Caelyx is a chlorhydrate of doxorubicin encapsulated within a pegylated liposome. The
liposomal formulation of doxorubicin (Caelyx) exhibits an altered pharmacokinetic profile
favouring the use of this drug formulation in brain tumour treatment. It has a longer
terminal half-life than free doxorubicin, and reaches greater concentration in the
tumour. Because of a decreased uptake by the reticuloendothelial system, the drug remains
in circulation much longer. This seems to be especially true in glioblastoma, where it
tends to accumulate in significant concentration due to the increase in
neovascularisation. This has been shown in experimental settings, as well as in the
clinic. Interestingly, because of its altered pharmacokinetic properties, it also
presents a reduced toxicity profile. The liposomal formulation of doxorubicin causes less
myelosuppression, nausea, vomiting and alopecia than standard doxorubicin. The
cardiotoxicity is also reduced.
However, even with the greater accumulation of the drug in the tumour cells, its rate of
BBB penetration when administered via IV infusion remains a limiting factor. Indeed, it
is too low to yield a significant concentration accumulation within the tumour site to
produce a therapeutic benefit.
Etoposide phosphate (Etopophos; Bristol-Myers Squibb Company, Princeton, NJ) is a
water-soluble prodrug of etoposide that is rapidly and completely converted to the parent
compound after intravenous dosing. The pharmacokinetic profile of either etoposide or
etoposide phosphate is identical. Toxicity and clinical activity are also the same. Since
etoposide phosphate is water soluble, solutions of up to 20 mg/mL can be prepared.
However, in high doses, it can only be given as a 5-minute bolus, in small volumes and as
a continuous infusion. Furthermore, it is not formulated with polyethylene glycol,
polysorbate 80 (Tween; ICI Americas, Wilmington, DE), and ethanol, and does not cause
acidosis when given at high doses. The easier-to-use etoposide phosphate represents an
improved formulation of etoposide.
Classically, etoposide must be diluted prior to use with sodium chloride (0.9% w/v) or
glucose (5% w/v) solutions to concentration of 0.2 mg/mL (i.e., 1 ml of concentrate in
100 ml of vehicle) up to 0.4 mg/mL (i.e., 2 ml of concentrate in 100 ml of vehicle).
Evidently, this cannot be something considered in a setting of IA administration, as the
volume administered would be excessive. Hence, the use of etoposide phosphate, for which
100-fold increased concentration can be prepared in a volume accessible for an IA
administration: 200 cc.
STUDY DESIGN
- - This clinical trial will be an open label randomized phase II study in
which intraarterial administration of carboplatin (400 mg/m2) combined with Caelyx (30
mg/m2) will be compared with intraarterial administration of carboplatin (400 mg/m2)
combined with etoposide phosphate (400 mg/m2).
Patients that have failed the standard
first line of treatment (Stupp protocol) and that are diagnosed with recurrent GBM will
be randomly distributed to one of the two second-line treatment paradigms using the block
randomization method. Each recruited patient will undergo maximal resection before
beginning treatments. Treatment cycles will be administered on a monthly basis until a
progression is identified on the magnetic resonance imaging (MRI) scan or until a total
of 12 cycles have been completed. The cohort will count 120 patients that will be divided
into two groups of 60 patients receiving one of the two chemotherapeutic combinations. As
to which of the two combinations will be best remains to be determined. For that reason,
data from our latest published clinical trial and patients treated with intraarterial
carboplatin at our institution will be used as benchmarks for baseline comparisons (OS of
11 months and PFS of 5 months from study entry).
AIM
- - By using carboplatin in combination with Caelyx or etoposide phosphate in the
setting of an IA infusion, our intention is to optimally deliver carboplatin-based
chemotherapy combinations to the brain beyond the BBB, and more specifically to the
tumour cells.
HYPOTHESES
- - In patients treated with either combination, our prediction is that this
will lead to an improved tumour response and control rate, with minimal impact on the
quality of life.
Our preliminary clinical data seems to support this hypothesis.
