A Randomized Phase II Study on Intraarterial Carboplatin Combined With Caelyx Compared to Intraarterial Carboplatin Combined With Etoposide Phosphate for Progressing Glioblastoma at First or Second Relapse

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 Once in the target vessel, a therapeutic agent can be administered via the catheter, that is later withdrawn at the conclusion of the procedure.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.