Endovascular intra-arterial infusion for cerebral glioblastoma

Dear Editor,

INTRODUCTION

The conventional therapies for glioblastoma (GBM) have limited therapeutic outcomes, so new treatment regimens are constantly being explored. Endovascular intra-arterial (IA) infusion for GBM is a promising novel therapeutic agent delivery procedure, but there is limited evidence-based research. The mechanism of IA infusion explored in clinical trials is mainly related to bypassing the blood–brain barrier (BBB) and the blood–brain tumor barrier, which represent an inherent challenge to medication delivery in GBM. [9]

Endovascular IA infusion is an investigational drug delivery procedure that involves selective catheterization of the GBM hypervascular tumor bed to achieve optimal concentrations of the therapeutic agent.[19] The success of IA infusion for chemotherapy delivery in tumors like retinoblastoma has spurred research into its application for GBM.[11]

ENDOVASCULAR IA INFUSION FOR CEREBRAL GBM

Endovascular IA cerebral infusion uses catheter-based delivery of therapeutic agents directly into tumor-feeding arteries, together with osmotic BBB disruption using mannitol.[9] Tumor drug levels from IA infusion can be 4-times higher than equivalent intravenous doses.[12] Agents frequently used in clinical trials for GBM endovascular IA infusion include carboplatin, bevacizumab, methotrexate, and temozolomide, with mannitol used for BBB disruption.[5]

The hypothesized potential advantage of this procedure, compared to approaches such as Carmustine Wafers (Gliadel^®) and Ommaya Reservoir, is that it covers a greater volume of tumor and its surrounding areas.[6]

We aim to explore the theoretical role and techniques surrounding IA delivery of therapeutic agents in five different settings of GBM treatment, comparing it to existing surgical delivery approaches available to the neurosurgeon [Table 1]. The pharmacokinetics and pharmacodynamics of such therapeutic agents are beyond the scope of this letter.

Table 1:

Comparison of methods of therapeutic agent delivery for different stages of newly diagnosed and recurrent GBM treatment.

• Preoperative endovascular IA infusion before surgical resection of GBM

• Single immediate session: Postoperative therapy in the surgical field after resection of GBM

• Multiple sessions: Postoperative therapy in the surgical field after resection of GBM

• Single immediate session: Postoperative therapy in the surgical field after resection of recurrent GBM

• Multiple sessions: Postoperative therapy in the surgical field after resection of recurrent GBM.

Preoperative endovascular IA infusion before surgical resection

Endovascular IA infusion for GBM in the pre-surgical phase mainly includes either preoperative embolization of tumor feeding arteries to reduce intraoperative blood loss[22] or IA infusion to deliver high concentrations of therapeutic agents before surgery, which has not been formally established as a standard treatment for GBM yet.[8] While the limited evidence surrounding preoperative endovascular embolization of GBM is promising, the results are tentative, based on low-level evidence, and lack confirmatory data from large-scale trials.[22] For endovascular IA infusion, recent investigational approaches involve combining magnetic resonance imaging with real-time angiographic perfusion images from super-selective microcatheter injection to precisely identify the arterial pedicle to GBM.[4] This modern technique could conceptually supplement preoperative embolization by facilitating the targeted delivery of medications that could shrink the tumor blood supply, improving postoperative outcomes. Preliminary findings show that endovascular IA infusion is feasible and safe, with a procedure-related complication rate of about 0.9% per procedure and no procedure-related deaths.[8]

Alternative medication delivery routes available to the neurosurgeon include the Ommaya reservoir and carmustine wafers (Gliadel^®). The Ommaya reservoir is a surgically implanted subcutaneous device that works by intrathecal/ intraventricular delivery of therapeutic substances such as chemotherapy for GBM. Like endovascular IA infusion, it is not recommended by the National Comprehensive Cancer Network as a standard treatment for GBM, and its use is mainly restricted to clinical trials.[16] It is not suited in the pre-surgical setting for newly diagnosed GBM, because its drug distribution mechanism is superficial with minimal parenchymal invasion, thereby making it inadequate to treat the primary tumor mass.[20]

Similarly, intracavitary Carmustine Wafers (Gliadel^®) are not utilized for GBM in the pre-surgical phase. Their use is limited to the postoperative GBM setting because they are implanted intraoperatively, following maximal safe resection of the tumor.[7]

Single immediate session: Postoperative therapy to the surgical field after resection of GBM

Postoperative endovascular IA infusion of agents can be performed as a single immediate session after resection of GBM. This could be done consecutively with resection in a hybrid operating room or more commonly in an endovascular suite immediately after craniotomy. The technical advantage of IA infusion over other routes, such as the Ommaya reservoir and Carmustine (Wafers) in the post-GBM resection setting, is that it can be precise in targeting the hypervascular resection cavity, potentially delivering therapeutic agents directly to regions supplied by a single cerebral artery.

There is no role for an intracavitary access device, namely, Ommaya, in GBM at initial diagnosis, because standard post-resection Stupp therapy (radiotherapy and temozolomide) is delivered systematically and through external beam, and incorporating an intracavitary device at this stage would increase complications without added benefit.[16] For Gliadel^® wafer, it is a carmustine-infused biodegradable polymer implant designed for direct delivery of chemotherapy into the tumor bed.[13] It is directly applicable in this scenario as it serves as a post-resection local agent delivery system. Moreover, clinical trials on Gliadel^® wafer have noted benefits, with the most significant one showing that carmustine wafer implantation (in combination with the Stupp regimen) can improve progression-free survival (adjusted hazard ratio [HR], 0.76 [95% confidence interval [CI]: 0.63–0.92], p = 0.005), not overall survival (OS).[17] Major side effects of these carmustine implants include cerebral edema, diminished wound healing, intracranial hypertension, seizures, and meningitis, which all need to be taken into consideration before Gliadel^® implantation after GBM resection.[13]

Multiple sessions: Postoperative therapy in the surgical field after resection of GBM

Multiple endovascular IA infusions are explored as a probable adjunct to standard chemoradiation in newly diagnosed GBM patients. Phase I/II Clinical trials have demonstrated hypothetical benefits of repeated endovascular IA infusion of bevacizumab added to the Stupp protocol for newly diagnosed post-resection GBM (median progression-free survival of 11.5 months, and median OS was 23.1 months, with 2-year OS of 45%) with no dose-limiting toxicities.[18] Another potential benefit of repeated endovascular procedures in multiple sessions after GBM resection is that they could help understand how the tumor responds to therapy, based on the hypervascularity of the resection area.

In comparison, the Ommaya reservoir serves as a direct method for delivering therapeutic agents over multiple sessions after GBM resection. It is a subcutaneous device connected to a catheter placed in the resection cavity, allowing flexible and multiple direct infusions of therapeutic agents into the tumor cavity.[23] It is reportedly tolerated with minimal systemic adverse effects; however, complications such as aseptic meningitis, headache, and infections have been described.[24] Common therapeutic agents studied in this procedure are mitoxantrone, doxorubicin, bleomycin, radiolabeled antibodies, and oncolytic viruses.[24] Despite the feasibility of Ommaya for multiple sessions, the major downside for infiltrative tumors like GBM is that the drug distribution is predominantly local, with poor penetration into infiltrating cavities.[2]

Single immediate session: Postoperative therapy to the surgical field after resection of recurrent GBM

In the setting of recurrent GBM, endovascular IA infusion is feasible, although the aggressiveness of recurrent GBM lessens the impact of any therapeutic intervention, including the delivery of therapeutic agents using the endovascular procedure. Current investigations surrounding endovascular IA infusion of therapeutic agents for recurrent GBM consider it to be a possible salvage option following failure of conventional therapies.[1,3]

Clinical trials on endovascular IA infusion after surgical resection of recurrent GBM have reported modest outcomes with radiographic evidence of tumor shrinkage in most patients who received either IA-infused bevacizumab or cetuximab; however, complications such as seizures, anaphylaxis, cerebral edema, rupture of the right anterior cerebral artery leading to subarachnoid hemorrhage, and left hemiparesis were documented.[1,3] Another obstacle associated with endovascular procedures in recurrent GBM is that, due to the radiation effect, the tumor blush is often not found.[14] Chen et al. described a perfusion-guided endovascular super-selective arterial infusion technique to increase the feasibility of targeted delivery of therapeutic agents for GBM.[4]

Carmustine wafers are directly applicable in the setting of recurrent GBM after maximal safe resection. A clinical trial in patients with recurrent high-grade glioma found a significant OS benefit in patients implanted with carmustine wafers, compared to placebo at re-resection (adjusted HR 0.67; 95% CI 0.48–0.95; p = 0.02).[15] Current guidelines support the implantation of carmustine wafers in recurrent GBM; however, implantation of Gliadel^® wafers might affect patients’ eligibility for other clinical trials.[16]

Multiple sessions: Postoperative therapy in the surgical field after resection of recurrent GBM

It is feasible to administer endovascular IA infusion of therapeutic agents in multiple sessions after resection of recurrent GBM. A phase II clinical trial demonstrated satisfactory outcomes after repeated monthly intracarotid carboplatin infusion for recurrent GBM, with the side effect of transient carotid spasms.[10] It is important to note that safety data for IA infusion in recurrent GBM are derived from clinical trials involving patients with preserved performance status (Karnofsky score of ≥60);[10] thus, these complication rates may not be generalizable to the broader recurrent GBM population. In addition, repeated IA infusion sessions involving general anesthesia, repeated contrast, and radiation exposure in the GBM population with a limited median survival time of approximately 11 months from salvage treatment may impose a cumulative burden that offsets the potential benefit.

Clinical investigations have shown that the Ommaya reservoir can be used to deliver numerous therapeutic agents in the setting of post-surgical recurrent GBM.[6] Although bacterial colonization is a recognized complication, clinical trials are increasingly incorporating Ommaya-based therapeutic delivery of agents in GBM.[21] In addition, while the central nervous system cancer guidelines do not formally approve its placement as a standard therapeutic option for recurrent GBM, it is recommended as an intrathecal therapy for leptomeningeal disease.[16]

In summary, endovascular IA infusion for GBM has potential applications in the treatment of GBM, whether at initial diagnosis or in the recurrent setting. We hypothesized five different settings where there could be conceptual benefits of endovascular IA infusion of therapeutic agents either to the tumor supply or to the hypervascular post-resection cavity. These include a single immediate session, as postoperative therapy in the surgical field after surgical resection of GBM; multiple sessions, as postoperative therapy in the surgical field after resection of GBM; a single immediate session, as postoperative therapy in the surgical field after surgical resection of recurrent GBM; and multiple sessions, as postoperative therapy in the surgical field after resection of recurrent GBM. This stepwise categorization could set the stage for future studies that aim to explore novel therapeutic agent delivery systems for both newly diagnosed and recurrent GBM, while simultaneously aiding in optimal endovascular agent selection for each phase of treatment.

Limitations

Endovascular IA infusion for GBM is a theoretical concept that needs to be investigated with future studies that delineate its efficacy, safety profile, and complications in the treatment of newly diagnosed and recurrent GBM.

CONCLUSION

This proposed five-stage framework may help guide future clinical trial design and optimize patient selection for endovascular IA infusion delivery strategies in newly diagnosed and recurrent GBM.

Ethical approval:

The Institutional Review Board approval is not required.

Declaration of patient consent:

Patient’s consent was not required as there are no patients in this study.

Financial support and sponsorship:

Nil.

Conflicts of interest:

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation:

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Disclaimer

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.