This animation shows the principle of the clinical trial. Under general anesthesia, a guide pedestal is secured to the animals skull over the tumor and is used to allow accurate placement of small glass catheters directly into the tumor. The experimental chemotherapy is infused into the tumor after which the catheter is removed and the animal is recovered from anesthesia. The pedestal is left in pace to allow for subsequent treatments.

 

 

 

 

Convection-Enhanced Delivery of Liposomal CPT-11 with Real-Time MRI in Canine Primary Gliomas.

A wide variety of methods have been employed to deliver therapeutic agents to brain tumors. Many strategies have involved systemic delivery of agents either orally or intravenously. Some drugs (eg standard chemotherapeutic agents) are relatively non specific with respect to their potential targets, whereas others (eg small molecule tyrosine kinase inhibitors such as Gleevac) may have a more precisely defined target despite the systemic delivery.

Even with the use of targeted therapies, the likelihood of significant systemic side effects is a major concern with drugs delivered in this manner. Ability of drugs to cross the blood brain barrier is also a factor that can significantly limit the efficacy of systemically delivered therapies, and many factors such as molecular weight, permeability of vasculature, drug stability and diffusion characteristics as well as tumor related factors are critical to attain effective cellular levels of anti tumor drugs. Local “targeted” delivery of therapies directly into tumor tissue has been advocated as a way to increase both the efficacy of many therapeutic agents whilst at the same time decreasing the likelihood of significant systemic toxicity. Therapeutic agents may be delivered directly at surgery following excision/debulking of tumors, or by stereotactic injection.

Recent advances in injection of agents by convection enhanced delivery (CED) (over several hours), have shown great promise, and may allow highly accurate and comprehensive delivery of therapeutics to a defined area of tumor and/or surrounding brain. Several human CED clinical trials have been undertaken for brain tumors, however one of the major limitations of the trials has been the inability to monitor and document the amount and accuracy of therapeutic delivery to the tumor. This has had serious implications when assessing efficacy, when delivery has not been documented!

As part of a collaborative project between the School of Veterinary Medicine UC Davis, and the Dept. Neurosurgery UC San Francisco, a clinical trial has been undertaken investigating the efficacy of liposomal CPT-11 (“Irinotecan”, a chemotherapeutic topoisomerase I inhibitor), administered directly into gliomas using CED and monitored in real time using co-infusion of a gadolinium marker and MRI. Preliminary data from dogs with CT biopsy diagnosed gliomas suggests that real-time imaging in future CED clinical trials (canine or human) is essential in order to define early leakage of infusates to non target tissues, to allow modification of infusions in real time, and to allow appropriate interpretation of response to therapy. Therapeutic response, defined by decrease in tumor volume (up to 80%), and modification of tumor phenotype (decreased Mib-1 index in infused vs non infused tumor based on histopathology) as well as documented adverse effects have also provided additional clinically relevant data for the development of intratumoral liposomal CPT-11 as a potential therapy in human gliomas.

 

 

CED of CPT-11 chemotherapy and an imaging agent (red) into an anaplastic oligodendroglioma (yellow) in a canine patient at the VMTH UC Davis.

pict

Infusion of a brain tumor (astrocytoma) in a Jack Russel Terrier. The tumor (arrows) can be seen on the left. Serial images of the infusion which is monitored in real-time while the dog is in the MR scanner. Monitoring allows the clinician to make sure that only the tumor is treated and that the optimal infusion is achieved.

Three months following treatment, the dogs tumor (circled) has decreased by approximately 80%. This dog with an anaplastic astrocytoma was clinically normal 1 year following treatment.

 

Infusion of a high grade oligodendroglioma in a Boston Terrier. The tumor boundry is marked by the arrows.

The top 2 rows show MRI slices of the tumor (arrows) before treatment. Following treatment the tumor has reduced by over 90% leaving an area of necrosis (n) with almost no visible tumor.

Untreated tumor (anaplastic astrocytoma) demonstrating a pleomorphic phenotype and high MIB-1 index. Following treatment the tumor phenotype became less pleomorphic and the MIB-1 index dropped dramatically, consistent with the clinical and imaging correlates of minimal tumor growth.

For more information about this clinical trial go to CPT-11 Clinical Trial