WO2007075912A2 - A system and method of administering a therapeutic material to brain tissue - Google Patents

Abstract

A system and method employing intraparenchymal pressure-driven delivery of a treatment material into brain tissue at risk for infiltrating tumor cells is provided. The system and method employ bulk flow as a driving force, by creating a positive pressure gradient using a pump. The pump is connected to an infusion catheter placed directly into brain parenchyma to be treated. The positive pressure is transmitted through this delivery system into the interstitial space of the brain parenchyma. Catheter positioning relative to anatomic landmarks and structures in the targeted tissue region plays a key role in optimizing the pressure-driven delivery of treatment material into the interstitial space.

Description

A SYSTEM AND METHOD OF ADMINISTERING A THERAPEUTIC MATERIAL TO BRAIN TISSUE

Inventors: David Jack. Croteau, Sandeep Kunwar, Jeffery Wayne Sherman and Amy Y. Grahn

Cross reference to related, applications

This application claims priority of US provisional application no. 60/752,966, filed December 22, 2005.

Field of the Invention

The invention relates to a system and method for distributing a therapeutic material into brain parenchyma, e.g.., for the treatment of disease caused by infiltrating tumor cells.

Background of the Invention The brain (see Figs. 1, 2, 3A and 3B) is lodged in the cranial cavity. Brain parenchyma (a term which refers to the essential functioning tissue components of the brain) has two main components: gray matter and white matter (see Fig. 2) . The gray matter refers to those parts of the brain that carry out the processing function of the brain. The white matter refers to those parts of the brain (and spinal cord) that are responsible for communication between the various gray matter regions and between the gray matter and the rest of the body. The brain, like all body tissue, is subject to disease, dysfunction, or damage. Well know,n are, e.g., Alzheimer's Disease, Parkinson's Disease, and Stroke. Also well known are the various forms of brain cancer, including primary brain tumors. Of the estimated 17,000 primary brain tumors diagnosed in the United States each year, approximately 60% are gliomas. Glioblastoma multiforme (GBM) is the most aggressive form of gliomas. Gliomas arise from the supporting glial cells in the white matter of the brain during childhood and in adults. In contrast to the uniform appearance of normal brain white matter under the microscope (Fig. 4A), gliomas (Fig. 4B) contain increased number of cells, atypical cells, dividing cells, necrosis and abnormal and numerous blood vessels. Gliomas can be graded microscopically from Grade I to Grade IV based upon microscopic appearance. Grade I, II, and III gliomas grow slowly over many years. However, Grade IV gliomas, called GBM, grow rapidly, invading and altering brain function. Most GBMs are lethal. GBM is by far the most common and most malignant of the glial tumors. Composed, of. poorly differentiated neoplastic astrocytes, glioblastomas primarily affect adults, and they are located preferentially in the cerebral hemispheres. Much less commonly, GBMs can affect the brain stem in children and the spinal cord. These tumors may develop from lower-grade gliomas, but., more frequently, they manifest de novo, without any evidence of a less malignant precursor lesion. GBM tumor growths, like other forms of primary brain tumors, do not spread throughout the body, but cause symptoms by invading and causing pressure on the normal brain tissue.

The first symptoms of GBM depend upon the area (i.e., lobe) of the brain first involved by the tumor. For example, impairment of recent memory, inattentiveness, inability to concentrate, behavior disorders, difficulty in learning new information, or a "flat personality" may occur when the frontal lobe brain region is involved. Visual impairments may occur when the temporal or occipital lobes are involved. More "silent" areas of the brain allow the tumors to become large before symptoms arise. In this case, increased pressure in the head may produce headache and rarely, visual loss from pressure on the optic nerves. The tumors also can irritate the brain, causing epileptic seizures. 5 GBM' s usually arise de novo (primary) or may develop from lower grade gliomas after many years (secondary) - Distinct genetic alterations in primary and secondary GBM' s have been identified. As a rule, they do not run in families.

10 Once symptoms occur, the tumor can be imaged by contrast-enhanced MRI (magnetic resonance imaging) scan. Progressive growth of the lesion on serial MRI scans differentiates a tumor from stroke. A PET (positron emission tomography) scan showing increased uptake of

15 glucose can also help separate a diagnosis of tumor from stroke. An open or needle biopsy provides tissue for microscopic diagnosis.

The treatment of GBM has evolved over the past 50 years. Currently, the treatment of glioblastomas is

20. palliative and includes surgery, radiotherapy, and chemotherapy.

GBM is an infiltrating disease (see Fig. 5) . Tumor cells spread into normal brain tissue and reside with normal cells. Radiation therapy and current forms of

25 chemotherapy can prolong survival but the tumor eventually progresses or relapses. With current surgical techniques, neurosurgeons can remove or resect as much as 100% of the visible tumor on imaging. Still, infiltrating GBM cells will remain undetected and scattered throughout

30 the brain tissue, both adjacent to and distant from the resection region. Delivery of targeted therapy into the brain to kill these infiltrating tumor cells remains one of the largest challenges to brain tumor therapy.

The challenge is due, in large part, to the Blood-

35 Brain-Barrier (BBB) . In the brain, the endothelial cells lining the capillaries fit so tightly together that certain substances cannot cross. The blood-brain barrier prevents many substances, such as toxins, that make it into the blood stream, from entering the brain. The blood-brain-barrier prevents the entry of a number of therapeutic agents that might be beneficial.

Despite current aggressive multimodality therapy aimed at infiltrating GBM cells, including radiation and chemotherapy, the median survival after initial diagnosis is only about nine to twelve months. GBM is the third leading cause of death from cancer in persons 15 to 34 years old.

There is a need for devices, systems, and methods for targeting the delivery of a therapeutic agent into brain parenchyma at risk for infiltrating brain tumor cells, such as GBM.

Summary of the Invention

The invention provides a system and method of • administering a therapeutic material into brain parenchyma .

According to one aspect of the invention, the system and method provide intraparenchymal distribution of a therapeutic material to a targeted tissue region by establishing a positive pressure gradient into the interstitial space of brain parenchyma. The positive pressure gradient distributes homogenous concentrations of the therapeutic material by convection (i.e., bulk flow) to the targeted tissue region. According to this aspect of the invention, the system and method includes catheter positioning guidelines. The guidelines are based upon criteria that take into account the presence of certain anatomic structures in the brain parenchyma, which could diminish or divert the convection of therapeutic material. Following the criteria, the physician plans and, places the catheter or catheters according to these anatomic structures. Adequate positioning optimizes the positive pressure-driven intraparenchymal distribution of treatment material to the targeted tissue region.

Other features and advantages of the invention shall be apparent based upon the accompanying description, drawings, and appended claims.

Description of the Drawings

Fig. 1 is an anatomic sagittal view, in section, of a healthy brain lodged within the cranial cavity.

Fig. 2 is an anatomic transverse section of the brain shown in Fig. 1, taken generally along line 2-2 in Fig. 1.

Fig. 3A and Fig. 3B are, respectively, an anatomic superior view and an anatomic lateral view of a brain, removed from the cranial cavity.

Fig. 4A and Fig. 4B are microscopic sections of brain white matter populated, respectively, by normal glial cells and malignant gliomas.

Fig. 5 is an anatomic sagittal section view of a brain having a solid tumor mass and a region outside the tumor mass that is- populated by a significant volume of infiltrating tumor cells (gliomas) .

Fig. 6 is a perspective front view of a system for delivering a therapeutic material through one or more catheters into a brain tissue region subject to a positive pressure, to distribute the treatment material within the brain tissue region by convective flow for a prescribed treatment period.

Fig. 7A is an exploded view of an infusion catheter and an associated stylet and trocar that can be used in establishing intraparenchymal access for the distribution of a therapeutic material using the system shown in Fig. Fig. 7B is an exploded view of the catheter shown in Fig. 7A and an associated compression hub connector that can be used in association with the system shown in Fig. 6.

Fig. 7C is an assembled view of the catheter and the compression hub connector shown in Fig. 7B, being shown in an exploded view with tubing and a pumping element, which, in use, are coupled in flow communication with the catheter for use in association with the system shown in Fig. 6-

Fig. 7D is an assembled view of the pumping element and tubing shown in Fig. 7C, now coupled via the hub connector to the catheter for use in association with the system shown in Fig. 6.

Fig. 8 is an anatomic sagittal view, in section, of a brain, like that shown in Fig. 1, with catheters placed in a brain tissue region for treatment by the system shown in Fig. 6. Fig. 9 is . a diagrammatic view of. a tumor-targeted treatment material (cintredekin besudotox) that can be used in association with the system shown in Fig. 6, diagrammaticalIy illustrating the selective mechanism by which cintredekin besudotox is internalized by a glioma cell, but not a normal glial cell.

Fig. 10 is an anatomic diagrammatic view of the intraparenchymal delivery of treatment material that the system shown in Fig. 6 provides to a tissue region that lays outside a resected solid tumor mass. Fig. 11 is a diagrammatic view of the distribution of infiltrating tumor cells in brain tissue outside a solid tumor mass, illustrating how the density of infiltrating tumor cells relative to normal tissue cells diminishes with distance from the margin of the solid tumor mass. Fig. 12 is an anatomic diagrammatic view of the intraparenchymal distribution of a treatment material within a brain tissue region by convective flow by infusing the treatment material through one or more catheters.

Fig. 13 is an anatomic diagrammatic sagittal view of anatomic structures or surgical tools in or near a targeted brain tissue region, the presence of which can disrupt or diminish the convective flow shown in Fig. 12, including (i) the brain surface through which the tip of the catheter enters; (ii) a deep sulcus or fissure that may lay in the trajectory of the catheter; (iii) the margin of a solid tumor mass resection cavity; (iv) an ependymal or pial surface that may lay in the trajectory of the catheter; <v) remnants of a residual solid contrast-enhancing tumor; and (vi) another infusion catheter.

Fig. 14 is an anatomic diagrammatic sagittal view of distances prescribed between the catheter and the anatomic structures or surgical tools shown in Fig. 13, which places the catheter in a position within a targeted brain tissue region where the positive pressure-driven convection shown in Fig. 12 can be optimized.

Fig. 15 shows a pamphlet of catheter positioning guidelines containing instructions for establishing prescribed separation distances between the catheter and the anatomic structures identified in Fig. 13 to minimize disruption of convective flow.

Figs. 15A to 15G are criteria excerpted from the pamphlet shown in Fig. 15 showing in pictorial form the separation distances prescribed, respectively, for (A) the brain surface through which the tip of the catheter enters; (B) a deep sulcus or fissure that may lay in the trajectory of the catheter; (C) a surface of a resection cavity through which the tip of the catheter enters; (D) the margin of a solid tumor mass resection cavity; (E) an ependymal or pial surface that may lay in the trajectory of the catheter; (F) remnants of a residual solid contrast-enhancing tumor; and (G) overlap between two infusion catheters.

Fig. 16 shows images indicative of a brain tissue region at risk for residual infiltrating tumor cells, which are downloaded into an MRI navigation system 40 during the catheter placement planning. Figs. 17 and 18 are anatomic views of the surgical placement of catheters shown in Fig. 8, in preparation for use in association with the system.

Fig. 19 shows a CT imaging used to confirm the proper positioning of catheters prior to use of the system.

Fig. 20 is a chart demonstrating that patients having two or more catheters positioned according to prescribed catheter positioning guidelines, such as those shown in Figs. 15A to 15G, prior to receiving convective flow intraparenchymal delivery of the treatment material as shown in Fig. 12, have a survival advantage.

Detailed Description of the Invention

Although the disclosure hereof is detailed and exact to enable those technically skilled to practice the invention, the physical embodiments herein disclosed merely exemplify the invention, which may be embodied in other specific structure . While the preferred embodiment has been described, the details may be changed without departing from the invention, which is defined by the claims .

I . System and. Method for Delivery of a Therapeutic Material into Brain Parenchyma Fig. 6 shows a system 10 for delivering a therapeutic material 12 into brain parenchyma, e.g., for the treatment of GBM. The system 10 includes one or more infusion catheters 14. The infusion catheters 14 are surgically implanted through -the calvaria into brain parenchyma at a targeted tissue treatment region (see Fig. 8) .

The system 10 also includes sources of one or more selected therapeutic materials 12. The sources 16 can comprise, e.g., syringes containing the therapeutic material 12 in pre-mixed solution, e.g., with phosphate buffered saline, normal saline (0.9 wt. %), or 0.2 wt. % human serum albumin in 0.9 wt. % saline.

The system 10 also includes one or more infusion pumps 18. The pumps 18 are coupled in flpw communication with the catheters 14 and the sources 16, e.g., by flexible plastic tubing 20. Operation of the infusion pumps 18 convey the selected therapeutic material 12 at prescribed flow rates from the sources 16 through the catheters 14 and into the targeted tissue treatment region.

A. The Catheters

The surgical placement of one or more infusion catheters 14 into brain tissue of a patient (as Fig. 8 shows) will be described in greater detail later. Fig. 7A shows the infusion catheter 14 prior to insertion. The catheter 14 takes the form of a conventional catheter that is capable of insertion into and reside within body tissue for various purposes, for example, as a ventricular catheter in the treatment of hydrocephalus (an excess buildup of CSF in the ventricles of the brain) or as a peritoneal catheter in the performance of peritoneal dialysis. Conventional catheters that can be used for these purposes and for the purposes of delivering a therapeutic material 12 into brain parenchyma include, e.g., those manufactured by Phoenix Biomedical Corp (e.g., an open-ended (end-port) catheter PIC-030) ; or IGN. Other types of catheters (e.g., side- port catheters, or tapering tip, or the like) may also be employed. However, use of an end-port catheter is 5 preferred, because it is believed that an end-port configuration may be optimal for establishing the desired convective flow conditions, when used in association with the system 10, as will be described in greater detail later .

10 The catheter 14 comprises a tubular body 22 made, e.g., of silicone elastomer. The tubular body 22 defines an interior passage or bore. A typical dimension for the catheter tube 22 suited for delivering a therapeutic material 12 into brain parenchyma can be, e.g., an inside

15 diameter of about 0.7 mm to 1.5 mm and an outside diameter of about .0.8 mm to 3.0 mm. . ■

The catheter tube 22 is desirably impregnated or otherwise marked with a radiopaque material, like barium, for visualization using computed tomography (CT) during

20 and after insertion. Radiopaque depth markings 24 are typically provided along the proximal length of the catheter tube 22. The markings 24 allow the physician to visually gauge _ the depth of penetration during and after insertion.

25 In the illustrated embodiment, as earlier described, the distal end of the catheter body desirably includes an open end or end port 26. Therapeutic material 12 conveyed into the catheter body 22 exits the end port 26 for distribution into tissue.

30. As Fig. 7A also shows, a stylet 28 (made, e.g., of stainless steel) is sized to reside within the bore of the catheter tube 22 during insertion. The stylet 28 provides column strength as the catheter tube 22 is inserted into tissue. The stylet 28 is withdrawn after

35 placement, as will be decribed later. As Fig. 7A further shows, a trocar 29 can. be provided that is sized to fit the end of the stylet 28.

The trocar 29 facilitates tunneling of the catheter under the skin for a secure attachment to the scalp, as -will also be described later.

As Figs. 7B and 7C show, a conventional compression hub connector 50 (made, e.g., by Vygon Neuro) is desirably coupled to the proximal end of the catheter tube 22 prior to infusion. The compression hub connector 50 includes a female hub 52 that fits into the proximal end of the catheter tube 22 and a male fitting 54 that screws into the female hub 52 to compression fit the hub connector 50 to the catheter tube 22 (see Fig. 7C) . The male fitting 54 includes a female luer connector 56, which is configured to receive a mating male luer connector 58. The male luer connector 58 is carried at the end of the infusion microtubing 20. In this way, the tubing 20 can be coupled to the catheter 14 in a secure and leak-free manner. A cap 60 is desirably provided (see Figs. 7B and 7C) . The cap 60 closes the luer connector 56 of the compression hub connector 50 prior to connection with the leur connector 58 of the infusion tubing 20. This closes the catheter 14 to allow a CT scan to be done to confirm placement of the catheters prior to coupling the tubing 20 and starting infusion.

As Fig. 7D shows, the cap 60 is removed when the male luer connector 58 of the infusion microtubing 20 is to be fitted into the female luer connector 56 of the hub connector 50.

As Figs. 7C and 7D show, the infusion microtubing 20 includes a connector 62 for coupling the microtubing 20 in flow communication with a pumping element 32 of the pump 18 (see Fig. 6) . The pumping element 32, is, during use, placed in association with a low volume pump controller 34 of the pump 18, as Figs. 6 and 7D show. In this way, the catheter 14 is coupled to the pump 18 in the manner shown in Fig. 6.

In Figs. 7C and 7D, the pumping element 32 is shown to be a syringe, e.g., a conventional 60 cc syringe. A prescribed dose of therapeutic material is drawn into syringe pumping element 32. In this arrangement, the syringe also comprises the fluid source 16, as previously described and shown in Fig. 6. In this arrangement, the associated pump controller 34 takes the form of a conventional low volume microinfusion syringe pump (e.g., a Medfusion™ 3500 Syringe Pump made by Medex) (which is also shown as the pump 18 in Fig. 6) . The syringe pumping element 32 will typically require priming before attachment of the infusion tubing 20.

Other types of low volume (i.e., microinfuson) infusion pump assemblies can be used for the pump 18. For example, instead of being a syringe pump, the pump 18 can comprise a low volume membrane pumping assembly, or a low volume peristaltic pumping assembly, or a low volume pediatric-type pumping assembly of various forms, fits, and functions. Of course, the specific configurations for the pumping element 32 and associated controller 34 will vary with the type of pump 18 selected. As Fig. 8 shows, the system 10 typically includes more than a single catheter 14, and thus more than a single pump 18 (see Fig. 6) , because the targeted tissue volume is typically too large to be treated effectively by a single catheter. B. The Infusion Pumps

The pumping element 32 is placed into association with a pump controller 34 to form the pump 18 (see Fig.

6) . The controller 34 operates the pumping element 32.

• The controller 34 also has an input to receive desired flow conditions from the operator (e.g., desired flow rate, time of infusion, etc.) . The controller 34 includes a microprocessor and software that monitors and governs operation of the pumping elements 32 to achieve the desired flow conditions. In this way, the system 10 regulates the flow of the therapeutic material 12 through the catheters 14 to the targeted tissue treatment region, to achieve the desired distribution of therapeutic material 12 in the targeted tissue treatment region. Further details of this aspect of the system 10 will be described later.

The system 10 operates for a prescribed treatment period, which can extend over a period of days. As Fig. 6 shows, system 10 is desirably arranged to allow the patient to ambulate while receiving treatment. For example, the infusion pump(s) 18 (i.e., the assemblies of the pumping element (s) 32 and the associated pump, controller (s) 34) can be mounted on a wheeled IV stand 3β in conventional fashion to follow the patient as he/she ambulates during treatment. C. The Therapeutic Material

The therapeutic material 12 can be selected among a variety of diagnostic and therapeutic agents, e.g., viruses, immunotoxins , enzymes, growth factors, and oligonucleotides. A desired therapeutic material 12 for delivery by the system 10 comprises a cytotoxic molecule that is attached to an antibody or growth factor that binds to a receptor on the targeted cells. The receptor is selected because it is present in substantially higher amounts on targeted cells than in normal cells (see Fig. 9) . Malignant gliomas (GBM) possess exceptionally high numbers of the receptor for Interleukin- 13 ("IL13R") which, in contrast, is expressed at low levels in only a few types of normal cells. A candidate therapeutic material 12 comprises a recombinant fusion protein consisting of a truncated bacterial toxin derived from Pseudomonas aeruginosa,

PE38QQR, fused to IL13. This agent is more completely described and preliminary cytotoxicity studies can be found in Int. J. Cancer 92, 168-175, which is incorporated herein by reference. This, i-n principle, allows for the selective or targeted distribution of the toxin to targeted cells (GBM), but not to healthy cells.

The foregoing sentence includes an "in principle" caveat, because it has been observed that the therapeutic material described, when administered systemically for treating malignancies in the central nervous system 10 such as malignant gliomas, does not demonstrate suitable efficacy. The poor overall efficacy of systemic chemotherapy for central nervous system 10 malignancies can be attributed to the exclusion by the blood-brain- barrier of most anti-tumor agents from the brain. Moreover, infiltrating tumor cells evade treatment by invading brain tissue adjacent to a tumor where they are further sheltered from exposure to any drug that does pass through the blood-brain-barrier. Thus, even those drugs that do penetrate the blood-brain-barrier fail to reach therapeutic concentrations in brain tumors and are generally metabolized and may produce undesirable side effects.

XI . Intraparenchymal Delivery of Therapeutic Material

It has been discovered that the therapeutic material 12 described above can provide efficacy in the treatment of GBM, if administered in a prescribed fashion by the system 10. More particularly, after resection of a solid tumor mass, the system 10 provides intraparenchymal infusion of the material 12 interstitially by convection flow through one or more catheters 14 that have been placed in prescribed positions relative to certain anatomic structures in or near the targeted tissue region .

The system 10 places the one or more catheters 14 in brain parenchyma in a tissue region that lays outside a solid tumor mass (see Fig. 10) . That is, the catheters 14 provide intraparenchymal delivery of material 12 to tissue around a surgical resection margin, and not intratumoral delivery within a solid tumor mass.

As a first step in the treatment process, before placement of the catheters 14, the solid tumor mass is fully or partially resected or removed. This leaves a resection cavity. The catheters 14 of the system 10 are placed in tissue at or near the margin of the resection cavity, in a region (i.e., the targeted tissue treatment region) , which is selected to encompass brain parenchyma at risk for infiltrating tumor cells. Here, the therapeutic material 12 is infused into brain parenchyma to selectively bind to and kill the residual infiltrating tumor cells, without harming the normal cells. In this way, residual infiltrating GBM cells can be targeted for eradication.

A. Locating Tissue at Risk for Residual

Infiltrating Tumor Cells

The targeted tissue region, i.e., where a clinically significant population of infiltrating tumor cells outside the solid tumor mass reside, can be identified in various ways.

Microscopic analysis of brain tissue surrounding a solid tumor mass (see Fig. 11) demonstrates that the ratio of residual infiltrating tumor cells to total cells in a given tissue region is a function of proximity to the outer boundaries of the resected solid tumor mass. For example, within a solid tumor mass (intratumoral), there is nearly a 1:1 ratio of tumor cells to total cells. In Fig. 11, the tumor tissue mass has a diameter of about 4 cm. Significant populations of infiltrating tumor cells still reside in the zones of tissue that neighbor the outer boundary of the solid tumor mass, e.g., 6% in a zone that lays within 2 cm of the outer boundary of the tumor tissue mass, and 1.8% in the next successive zone 2-4 cm from, the outer boundary of the solid tumor mass. In zones more distant, the population of infiltrating tumor cells drops significantly (to a ratio of 1:1000) .

The density distribution of residual infiltrating tumor cells in regions proximal to the solid tumor mass, and the diminution of the population of infiltrating cells in more distant regions, can serve as a template for planning the placement of the catheters and the operational parameters of the system 10. The template makes possible a distribution of the therapeutic material 12 to target a clinically significant volume of tissue outside the resected solid tumor mass, where significant populations of infiltrating tumor cells reside.

Magnetic resonance imaging (MRI) can also be used to locate regions of tissue where larger populations of residual infiltrating tumor cells are likely to reside outside the solid tumor mass. It is believed that tissue regions that display, on MRI, T2/FLAIR hyperintense signal abnormalities, are indicative of the presence of significant populations of residual infiltrating tumor cells. The identification of these areas by MRI, and the inclusion for additional targeting of the largest white matter areas adjacent to them, can also serve as templates for planning the desired intraparenchymal distribution of therapeutic material 12 by the system 10. B. Distribution of Therapeutic Material by Bulk

Flow (Convection)

The system 10 establishes and maintains flow conditions that distribute the therapeutic material 12 in a homogenous way to the targeted tissue treatment region, in a manner that bypasses the blood-brain-barrier as well as minimizes systemic exposure to and plasma dilution of the therapeutic material 12.

The flow conditions established by the system 10 do not rely upon a concentration gradient of therapeutic material 12 to deliver the material by diffusion. Instead, the system 10 establishes flow conditions that establish a positive pressure gradient into the interstitial space of the brain parenchyma targeted for treatment (see Fig. 12) . The positive pressure gradient provides parenchymal distribution of material 12 by convection (i.e., by bulk flow) to the targeted volume of tissue.

The establishment of conditions conducive to convection flow makes possible the parenchymal distribution of therapeutic material 12 in homogenous concentrations to larger and clinically significant volumes of tissue than with diffusion (i.e., by use of a concentration gradient) . The blood-brain-barrier is by- passed, and systemic exposure and plasma dilution are minimized.

To establish a pressure gradient, the system 10 operates the pumping components 18 at a selected targeted flow rate, or within a selected targeted range of flow rates. The targeted flow rate, or targeted range of flow rates, can be selected based upon empirical data, taking into account certain physical parameters of the system 10 that affect convection flow, such as the viscosity of the therapeutic material 12, the physical dimensions of the catheter 14, pressure drops through the flexible tubing 20, and the morphology of the targeted tissue. The targeted flow rate, or targeted range of flow rates, that is selected produce the desired positive pressure gradient having a magnitude sufficient to transport the treatment material by convection into the interstitial space of the brain parenchyma where the targeted tissue resides. The flow rate or range of flow rates selected also takes into account physiologic factors, which prescribe an upper pressure limit, to avoid tissue injury, to minimize infusate backflow and to prevent intracranial pressure increase.

Flow rates of at least 0.03 ml/hr and up to 1 ml/hr will establish the desired pressure conditions conducive to convection in most brain tissue. These flow rates and the resulting pressure gradient are well tolerated in brain tissue. The Example that later follows discloses an operative flow rate of 0.75 ml/hr for all catheters (maximal flow rate for one catheter is 0.540 ml/hr). C. Catheter Placement A technique known as "convection-enhanced delivery" (CED) has been used to achieve intratumoral distribution of a therapeutic material into a solid tumor tissue. Devices for convection-enhanced, intratumoral drug delivery of materials are known, e.g., U. S. Pat. No. 5,720,720; U.S. Patent Publication 2005/0002918; Am. J. Physiol. 277, R1218- 1229; Proc. Nat ' 1 Acad. Sci. (1994) 91, 2076-2080; J. Neurosurg. (1995) 82, 1021-1029.

In intratumoral delivery using CED, catheter placement is straightforward and intuitive: the catheter is placed within the tumor mass. Thus, in intratumoral delivery using CED, attention has been given to the minimization of backflow along the catheter track, and/or catheter infusion rate optimization, and/or new catheter configurations, to promote the desired distribution of therapeutic material by convection flow within the confines of the tumor.

However, in intraparenchymal delivery using convective flow, catheter placement is neither straightforward nor intuitive. It has been discovered that, when therapeutic material 12 (or any infusate) is delivered by the establishment of convection flow conditions into the brain, the placement of the catheter or catheters in the targeted tissue region must take into account the presence of certain anatomic structures in the convection path. The presence of these anatomic structures can disrupt or diminish convection flow and can significantly affect the effectiveness of intraparenchymal infusate delivery, both, in terms of the volume of distribution as well as the homogeneity of the distribution in the interstitial space.

The system 10 identifies and then takes into account the presence of these anatomic structures in the convection path. These anatomic structures constitute landmarks relative to which adequate catheter positioning can be gauged and rated. The system 10 desirably instructs placement of the catheter or catheters relative to each other and relative to these anatomic landmarks to take full advantage of the positive pressure-driven distribution of the treatment material to the brain parenchyma targeted for treatment. 1. The Criteria

Fig. 13 shows anatomic structures in brain parenchyma, the presence of which can disrupt or diminish convective flow. It is the presence of these structures in the convection path that is taken into account by the system 10 when placing a given catheter.

The anatomic structures include (i) the brain surface through which the tip of the catheter enters, and through which infusate leakage can occur; (ii) a deep sulcus or fissure that may lay in the trajectory of the catheter, which can impede or divert flow along the convection path; (iii) the boundary of a solid tumor mass resection cavity, which also can impede or divert flow along the convection path; (iv) an ependymal or pial surface that may lay in the trajectory of the catheter, which marks the boundary of a ventricle or CSF compartment into which the treatment material can .leak, thereby disrupting and diverting the intended distribution; (v) remnants of a residual solid contrast- enhancing tumor, from which infused treatment material can significantly efflux and lead to an erratic and heterogeneous distribution; and (vi) another infusion •catheter,- which . can cause convection paths to overlap and be disturbed. The system 10 includes instructions or criteria 38 for catheter placement. The criteria 38 identifies each of the anatomic structures as a landmark (x) relative to which catheter placement is desirably gauged. The criteria 18 prescribes recommended minimum separation distance (SD(x)) between each landmark and the treatment dispensing region of the , catheter (which, in the illustrated embodiment, lays at the distal tip) .

For a given anatomic landmark (x) , the separation distance (SD (x) ) defines the shortest interval of interstitial tissue that should .lay between the distal tip of the catheter and the respective anatomic landmark (x) . Maintaining an actual separation distance equal to or greater than the prescribed separation distance SD (x) for all landmarks minimizes the likelihood that any landmark will disturb or disrupt the intended convection distribution path. In this way, the criteria 38 minimizes disturbance or disruption of convective flow.

In the illustrated embodiment, the criteria 38 defines the following group of separation distances (SD(X) ) :

As Fig. 14 shows, the criteria 38 make possible recommended separation distances to guide the placement and navigation of a given catheter in brain parenchyma. The recommendations help to position the catheter in a tissue region where optimal parenchymal delivery of treatment material by pressure-driven convection can occur, by minimizing disruption or diversion due to localized anatomic structures or the presence of other surgical tools (e.g., another catheter).

The magnitudes of the various separation distances SD (i) to SD (v) can use as a benchmark or baseline a nominal backflow distance derived for the given catheter or class of catheters. The nominal backflow distance comprises the expected distance that infusate introduced at a given flow rate can be expected to flow back along the catheter tissue track. The nominal backflow distance can be derived from physiologic and animal modeling, as well as convection and tissue parameters e.g., upon the viscosity of the therapeutic material 12, the physical dimensions of the catheter 14, the morphology of the targeted tissue in which the catheter is placed, and the operation parameters for the system 10 (i.e., the commanded flow rate) . For example, a relationship for the finite backflow- distance along a given catheter in pure gray matter (x(m)) has been determined from a mathematical model based on Stokes flow, Darcy flow in porous media, and elastic deformation of the brain tissue

(Morrison et al., Focal Delivery During Direct Infusion to Brain: Role of Flow Rate, Catheter Diameter, and

Tissue Mechanics, Am J Physiol. 1999 Oct;277(4 Pt

2) :R1218-29) . Other mathematical models can be used. The nominal backflow distance can comprise an average backflow distance measured or derived for a family of catheters having similar physical characteristics. The various separation distances are established by scaling the nominal backflow distance larger or smaller based upon the- morphology of the particular anatomic structure, as well as empirical and/or intuitive considerations.

For example, in the illustrated embodiment, the derived nominal backflow distance is 2.0 cm. Based upon this numerical magnitude for nominal backflow distance, the criteria 38 scales the separation distances as follows :

Separation Magnitude Morphologic, Empirical , Distance and/or Intuitive Considerations

SD(V) >0.0 cm The magnitude of this Tumor Remnant separation distance is not Distance directly related to a scaling of the nominal

See Fig. 15F backflow. Significant efflux through disrupted blood-brain and blood- tumor barriers can be expected when the therapeutic material 12 is administered directly into the residual solid contrasting-enhancing component of a tumor (intratumoral) , with also heterogeneous and limited distribution outside the solid tumo 1r. To avoid such disruption, it is believed that the catheter tip should be positioned just adjacent j to but not directly ' into any solid residual contrast- enhancing tumor, whenever applicable . Separation Magnitude Morphologic, Empirical , Distance and/or Intuitive

Considerations

SD(vi) ≥ 2.0 cm The magnitude of this

Catheter Distance separation distance is not directly related to a

See Fig. 15G scaling of the nominal backflow. Instead, a typical volume of distribution extent about a given catheter tip is used. The magnitude of SD (vi) is- based upon this. When empirical and clinical data demonstrates that the volume of distribution extends approximately 1 to 2 cm radially with an elliptical shape around the distal tip of the catheter (which is believed to be typical, SD (vi) is set at or beyond the outer boundary of the distribution pattern, to avoid or minimize overlap between adjacent catheters and the consequent disruption of convection flow.

The exact numerical values that the criteria 38 assign may vary depending on the type of catheter and other factors affecting the propensity for backflow and may be further adapted based on clinical information.

The format that the criteria 38 takes can, of course, vary. The criteria 38 can be placed in a written format (see Fig. 15), e.g., in booklet form, and be presented to the physician with the system 10. The criteria 38 can also be supplied separately. The criteria 38 can be embodied in separate instruction manuals, or in video or audio tapes, CD's, and DVD's. The criteria 38 can also be available through an internet web page. As Figs. 15A to 15G show, the criteria 38 can include pictorial instructions illustrating the separation distances. III. Use of the Criteria

The criteria 38, described above, establish guidelines for optimal catheter positioning to minimize backflow and outflow of infusate along the catheter track and through surfaces or anatomic structures (i.e., the catheter placement landmarks) in the targeted tissue treatment region during positive pressure-driven intraparenchymal delivery by the system 10. The criteria 38 thereby make it possible to optimize the volume of positive pressure-driven intraparenchymal distribution of the treatment material to the brain tissue targeted for treatment . The criteria 38 can be applied using conventional planning navigation MRI. Target and catheter trajectory can be selected based upon the criteria 38 from images obtained from the navigation MRI and reviewed to ensure they fulfill the guidelines. If not, new target and catheter trajectory are desirably selected to conform to the criteria 38 as closely as possible, given the morphology and topography of the targeted tissue region.

Following planning, catheter placement can be performed in conventional ways using the pre-determined stereotactic coordinates and can be adjusted as needed based on intra-operative findings. Actual catheter positioning is desirably evaluated by imaging prior to beginning infusion of the treatment material .

A. Planning Catheter Placement The criteria 38 can be used in association with MRI and convention neurosurgical navigational systems to guide placement of the catheters. Physicians can be advised in the criteria 38 to typically allow one to two hours to plan all catheter trajectories for up to four catheters (i.e., approximately 20-30 minutes per catheter) .

The criteria 38 desirably teaches the selection of a tissue region or region where clinically significant populations of infiltrative tumor targets reside and the subsequent placement of catheters to' distribute treatment material into the region or regions. MRI can be performed just prior to catheter placement including T2-weighted or FLAIR images, to identify areas at greatest risk for residual infiltrating tumor, including reliance upon hyperintense signal abnormalities and selection of the largest areas of white matter adjacent to the surgical resection cavity. Tl-weighted images with and without gadolinium can also be used if residual solid contrast- enhancing tumor is suspected. The potential volume of distribution (about 1 to 2 cm radius from catheter tip, as discussed above) should also cover the resection margins whenever possible, as the infiltrating tumor density is highest in that region (as Fig. 11 shows) .

Fig 16 illustrates a conventional navigation system 40 using the criteria 38 in association with MRI or other input sources. The navigation system 40 comprises a programmed processor 70 operatively associated with a memory 72, keyboard 74 and output device 76, such as a display monitor or printer. The navigation system 40 may comprise a personal computer or server or the like. An input/output (I/O) interface 78 operativβly connects source devices 80 to the navigation system 40. An MRI is an example of a source device.

The memory 72 stores a software planning program for implementing the criteria 38 to automatically plan catheter placement. MRI images are desirably downloaded from the source device 80 into the navigation system 40 before target selection. To determine recommended catheter placement, the software program may implement a known model and formulae such as are described in Am. J. Physiol. 277, R1218- 1229, mentioned above, or Am. J. Physiol. 266, R292- 305, adapted based on the criteria 38. The software program analyzes patient specific data in the form of brain flow pathways and the like from the MRI images using the models, formulae and criteria 38 to select a tissue region or region where clinically significant populations of infiltrative tumor targets reside and the subsequent placement of catheters to distribute treatment material into the region or regions. MRI images including overlays illustrating the catheter placement are then illustrated in images displayed on the display 76, as shown.

Targets, trajectories and entry points are desirably selected using all three MRI planes and the planning software of the MRI navigation system 40. The trajectory is desirably reviewed with the inline and probe's eye view to ensure compliance with the optimal catheter positioning criteria 38. If positioning criteria are not met, the target and/or entry point is desirably modified until optimal planning is achieved.

B. Performing Catheter Placement

As Fig. 17 shows, scalp and skull entry points are determined in conventional fashion using the navigation system 40 and planning MRI. Separate incisions and burr holes are usually necessary for each catheter 14. Based upon the separation distance SD (i) - i.e., the estimated distance from catheter tip target to entry point (brain surface level) — the physician locates and marks the distance 42 on the catheter 14 corresponding to the separation distance SD(i). In this way, the level of the entry point (brain surface) is determined and the catheter is placed at the exact depth. It may be useful to again mark the- catheter i4 at .the dural and skull- levels, such that, after placement of the catheter 14 and during closure, it is possible to confirm that the catheter 14 has not moved.

A conventional frame guide 44 or a frameless trajectory guide tightly fitting the outer diameter of the catheter 14 can be used to provide fixation, to facilitate accurate catheter insertion. For example, a Navigus TG8000 device (with 2 mm adapter) may be used for this purpose. The frame guide angle is adjusted using the navigation system 10 to ensure that actual trajectory along which the catheter 14 will be passed matches the planned one. Typically, an angle greater than 30° from the orthogonal plane should be avoided, as this may decrease the accuracy of positioning. If a frameless trajectory guide is used, it should be positioned as close as possible to the skull to minimize catheter movement.

With the catheter stylet 28 inserted within the catheter after the latter has been soaked in normal saline or a more viscous solution such as bacitracine to help lubrication for insertion and removal of the stylet and consequently prevent catheter movements, the catheter 14 is passed along the set trajectory using the guide 44, until the pre-determined mark 42 — indicating SD (i) — reaches the entry point level (i.e., the mark 42 should be at the brain surface) . Desirably, the catheter 14 and stylet 28 are introduced as one unit, to keep the stylet from protruding from catheter distal end during passage.

. After the catheter 14 has been inserted to the appropriate depth, it is temporarily secured to prevent movement. The stylet 28 is removed from the catheter tube. The. stylet 28 is desirably removed slowly, while continuously irrigating the proximal catheter end. In this way, as the stylet 28 is removed, fluid rather than air -.is drawn into the catheter lumen.

The frame 44 is removed, and the catheter 14 is checked for exact depth. The dura is closed, if necessary. Desirably, the catheter 14 is not stitched to any structure .

As Fig. 18 shows, the catheter 14 is stabilized for use by being tunneled subcutaneously for several centimeters from the entry point, e.g., using the trocar

29 (Fig. 7A) fitting the catheter's inner diameter. The physician should mark the catheter 42 at the scalp skin edge level, so any catheter movement can be detected. A sterile marking pen can be used for additional circumferential marking, if necessary or desired.

The scalp entry point is closed in a conventional fashion without stitching the catheter directly.

As Fig. 18 shows, each catheter can be secured with nylon sutures using, e.g., a three-point fixation in a loop fashion with a first suture at the entry point. A purse string suture is used if the exit wound is larger than the catheter.

Each catheter 14 is slowly primed over one to two minutes with preservative free normal saline (0.9% NaCl) using a tuberculin syringe. The volume should equal the void volume of the catheter (approximately 0.3 cc for a

30 cm catheter with a 1.0 mm ID) in addition to the compression hub connector volume (approximately 0.1 cc) . The purpose of priming is to remove air in the system 10. Air can significantly alter convection kinetics of the infusate as it leaves the catheter tip.

The catheter 14 with the compression hub connector

50 is preferably closed with a cap 60, as previously described and as shown in Fig. 7C, to allow CT scanning to be performed to confirm placement of the catheter 14.

The catheter number is desirably marked with a sterile pen at its proximal (externalized) end. Sterile labels (steristrips) are desirable describing respective target location when two (2) or more catheters are used. C. Confirming Catheter Placement

Catheter positioning can be evaluated with postoperative imaging (CT scan or MRI) (see Fig. 19) . The cap 60 can be removed and the tubing 20 connected, as shown in Fig. 18, once desired placement is confirmed. Repositioning of the catheter after this time is desirably avoided, as this may significantly alter convection kinetics .

By coupling of the syringe pump element 32 (after priming) to the tubing 20, and by coupling the syringe pump element 32 to the syringe pump controller 34, as Fig. 12 shows, infusion can commence.

Example

During a Phase 1 trial, patients (n=42) with recurrent GBM were treated with a system 10 as shown in Fig. 6. The treatment material comprised cintredekin besudotox.

Under the treatment protocol, the cintredekin besudotox was infused intratumorally into a GBM solid tissue mass for two days, at a total cintredekin besudotox dose per day of 4.8 μg. On the seventh day, the tumor was resected. At the time of resection, catheters were placed in brain parenchyma to target a volume of tissue at risk for residual infiltrating GMB cells for intraprenchymal delivery of cintredekin besudotox for a treatment period of four additional days. The system 10 distributed the treatment material in brain parenchyma by a positive pressure gradient to the targeted volume of tissue. More particularly, the cintredekin besudotox was delivered in brain parenchyma at a concentration of between 0.25 μg/iαl to 0.5 μg/rαl (which was the maximum tolerated dose) - A total flow rate of 0.75 ml/hour was prescribed and maintained, leading to a total delivered fluid volume of 18 ml per day, 72 ml total (i.e., an cintredekin besudotox dose per day of 4.5 μg to 9 μg, 18 μg to 36 μg total depending upon the concentration) . The flow rate was well tolerated.

It was demonstrated that pressure—driven delivery of cintredekin besudotox at an intraparenchymal concentration of 0.25 μg/ml to 0.5 μg/ml during a treatment period of four days, at a total flow rate of 0.75 ml/hour, was well tolerated.

A retrospective evaluation of catheter positioning, in which actual catheter position was scored and rated using a scoring system that was based upon initial criteria 38 was performed. It was subsequently observed that ependymal surfaces are not as resistant as pial surfaces and the distance requirement was increased from 0.5 to 1.0 cm. The scoring system initial criteria 38 were: (1) SD(i) and SD(ii): Depth ≥ 2.5 cm from brain surface or any deep sulcus or from resection cavity wall if placed through the resection cavity.

(2) SD (iv) : Catheter tip ≥ 0.5 cm from any ependymal or pial surfaces (3) SD(iii) : Catheter tip ≥ 0.5 cm from the resection cavity walls

The following Table sets forth the scoring system:

Statistical analyses were conducted to identify any correlation between adequate catheter positioning and patient survival. Fig. 20 summarizes the outcome. Patients having two or more catheters that were scored 1 or 2 had a median survival of 51.7 weeks (95% CI, 36.1- 78.0) (better than the median survival of the entire study of 44.0 weeks (95% CI, 36.1-52.4)). Patients in which none or only one of the catheters were scored 1 or 2 had a lesser median survival of 39.3 weeks (95% CI, 29.0-51.9) .

The Example demonstrates that patients having two or more catheters positioned according to criteria 38 (based on the score system outlined above), and which receive convective flow intraparenchymal delivery of the treatment material, have a survival advantage presumably related to optimal drug distribution. The criteria 18 for catheter placement makes possible an optimal intraparenchymal distribution of treatment material 12 to provide an antitumor effect in brain parenchyma infiltrated with tumor cells.

While the system and method have been specifically described in the context of the treatment of conditions affecting brain tissue, it should be understood that the principles and concepts relating to pressure—driven intraparenchymal distribution and proper catheter position, as described, may be applicable to the intraparenchymal treatment of tissue in other regions of the body. Other embodiments and uses of the invention will be apparent to those skilled in the technique from consideration of the specification and practice of the invention disclosed herein. The specification and examples should be considered exemplary and merely descriptive of key technical; features and principles, and are not meant to be limiting. The true scope and spirit of the invention are defined by the following claims. As will be easily understood by those of ordinary skill in the art, variations and modifications of each of the disclosed embodiments can be easily made within the scope of this invention . as defined by the following claims .

Claims

What is claimed is:

1. A system of administering a therapeutic material to brain tissue, said system comprising: at least one infusion catheter sized and configured for placement in a brain tissue region outside a resected solid tumor mass; a source of a treatment material for brain tumor cells; ■ ^{■ •} a pump coupled to the source and to the infusion catheter, wherein said ^• pump infuses- the treatment material through the catheter and into the brain tissue region subject to a positive pressure and distributes the treatment material within the brain tissue region by convective flow for a prescribed treatment period; and instructions for establishing prescribed separation distances between the catheter and at least two identified anatomic structures present in or near the brain tissue region, wherein said instructions minimize disruption of the convective flow.

2. The system of claim 1 wherein the instructions include, for each identified anatomic structure, a prescribed minimum separation distance between the catheter and the identified anatomic structure.

3. The system of claim 1 wherein •' the instructions identify at least two anatomic structures selected from a group consisting essentially of (i) a brain surface, (ii) a deep sulcus or fissure, (iii) a boundary of a tumor resection cavity or ependymal ^•surface, (iv) a pial surface, and (v) a residual solid contrast—enhancing tumor.

4. The system of claim 1 wherein the instructions include a prescribed minimum distance relative to a second catheter placed in or near the brain tissue region.

5. The system of claim- - 1 wherein the instructions include a catheter placement method comprising the steps of conducting a first evaluation of the planned position of the catheter based upon a first one of the separation distances, conducting a second evaluation of the planned position of the catheter based upon a second one of the separation distances, and changing the position of the catheter based upon the evaluations until both prescribed separation distances are established.

6. The system of claim 1 further including at least two infusion catheters.

7. The system of claim 1 wherein the treatment material includes interleukin 13 (IL13) bound to a cytotoxic agent.

8. A method for administering a therapeutic material to brain tissue, said method comprising the steps of: identifying a brain tissue region outside a resected solid tumor mass; placing at least one infusion catheter within the brain tissue region; establishing prescribed separation distances between the catheter and at least two identified anatomic structures present in or near the brain tissue region; and distributing a treatment material within the brain tissue region by convective flow for a prescribed treatment period by infusing said treatment material through the catheter and into the brain tissue region subject to a positive pressure.

9. The method of claim 8 wherein the at least two anatomic structures are selected from a group consisting essentially of (i) a brain surface, (ii) a deep sulcus or fissure, (iii) a boundary of a tumor resection cavity or ependymal surface, (iv> a pial surface, and (v) a residual solid contrast-enhancing tumor.

10. The method of claim 8 further including the step of establishing a prescribed separation distance between the catheter and a second catheter placed in or near the brain tissue, region.

11. The method of claim 8 wherein the step of establishing prescribed separation distances between the catheter and at least two identified anatomic structures present in or near the brain tissue region includes conducting a first evaluation of a planned position of the catheter based upon a first one of the separation distances, conducting a second evaluation of the planned position of the catheter based upon a second one of the separation distances, and changing the position of catheter based upon the evaluations until both prescribed separation distances are established.

12. A method for administering a therapeutic material to brain tissue, said method comprising the steps of: prescribing a desired clinical outcome including an intraparenchymal distribution through an infusion catheter of a treatment material by convective flow into a brain tissue region outside a resected solid tumor mass; and placing the infusion catheter within the brain tissue region based upon catheter positioning criteria designed to achieve the desired clinical outcome by prescribing separation distances between the catheter and at least two anatomic structures in or near the brain tissue region.

13. A system of determining catheter placement for administering a therapeutic material to brain tissue using at least one infusion catheter sized and configured for placement in a brain tissue region outside a resected solid tumor mass, said system comprising: an input device providing information representing select brain areas at risk for residual infiltrating tumors ; a programmed processing system implementing instructions using the provided information for establishing prescribed separation distances between the catheter and at least two identified anatomic structures present in or near the brain tissue region, wherein said instructions minimize disruption of convective flow; and an output device operatively associated with the programmed processing system providing recommendations for catheter placement using the prescribed separation distances.

14. The system of claim 13 wherein the input device comprises an MRI.

15. The system of claim 13 wherein the output device comprises a display monitor.

16. The system of claim 13 wherein the instructions include, for each identified anatomic structure, a prescribed minimum separation distance between the catheter and the identified anatomic structure .

17. The system of claim 13 wherein the instructions identify at least two anatomic structures selected from a group consisting essentially of (i) a brain surface, (ii) a deep sulcus or fissure, (iii) a boundary of a tumor resection cavity or ependymal surface, (iv) a pial surface, and (v) a residual solid contrast-enhancing tumor .

18. The system of claim 13 wherein the instructions include a prescribed minimum distance relative to a second catheter placed in or near the brain tissue region.

19. The system of claim 13 wherein the instructions include a catheter placement method comprising the steps of conducting a first evaluation of the planned position of the catheter based upon a first one of the separation distances, conducting a second evaluation of the planned position of the catheter based upon a second one of the separation distances, and changing the position of the catheter based upon the evaluations until both prescribed separation distances are established.