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Blood-brain barrier disruption for the treatment of malignant brain tumors: the national program.

Introduction

The blood-brain barrier (BBB) is made up of tight junctions which line the central nervous system capillaries.[5] These tight junctions effectively exclude substances that are lipid insoluble and those of a molecular weight greater than 180 daltons.[16] The molecular weight of most chemotherapeutic agents is between 200 and 1200 daltons. Therefore, most of the currently available therapeutic agents for the treatment of malignant brain tumors are unable to cross the barrier. This creates a discouraging clinical dilemma, particularly since the incidence of malignant brain tumors in the United States is rapidly increasing. Currently, approximately 17,000 individuals are annually diagnosed with a brain tumor.[18] In addition, one fourth of all childhood cancer deaths are caused by brain cancer.[20]

Osmotic opening of the BBB enhances chemotherapy delivery for patients with malignant brain tumors. This article discusses the technique of osmotic opening of the BBB pioneered by Dr. Edward Neuwelt, the National BBB Program, the role of advanced practice nurses in the care of patients undergoing this treatment, results thus far with enhanced chemotherapy delivery in a variety of brain tumors and future directions of the National BBB Program.

Osmotic Opening of the Blood-Brain Barrier

The technique of blood-brain barrier disruption (BBBD) pioneered by Neuwelt and collaborators at Oregon Health Sciences University involves an osmotic process.[16] When capillary endothelial cells are exposed to a hyperosmolar solution, the cells shrink secondary to osmosis. This shrinkage places stress on the tight junctions which line the capillaries. With this stress, the tight junctions are pulled apart (Fig 1). This is the period of time when the blood-brain barrier is considered "open." This opening of the barrier is transient and reversible. Transient, since the blood-brain barrier normally provides a protective role by excluding toxic substances from the brain, and reversible, because ideally the barrier should return to a normal baseline and be susceptible to osmotic opening again and again.

[Figure 1 ILLUSTRATION OMITTED]

In order to deliver drug to the proliferating edge around the tumor, the entire vascular distribution supplying the tumor and surrounding brain needs to be disrupted. This is particularly the case when multiple tumor foci are present, as in primary CNS lymphoma, glioma and breast and lung tumor metastases.[11] In several experimental brain tumor models, BBBD by the bolus administration of mannitol has resulted in increased drug delivery to both tumor and the area around the tumor 10 to 100-fold.[16]

The National Blood-Brain Barrier Program

Oregon Health Sciences University (OHSU) is the coordinating center for the National Blood-Brain Barrier Program. The technique of osmotic opening of the barrier as well as the chemotherapy protocols and practice guidelines have been developed by the coordinating center with input from the universities participating in the National Program. The universities include: University of Oklahoma, Oklahoma City; University of Missouri, Kansas City (Children's Mercy and Trinity Lutheran Hospitals); James Cancer Hospital of the Ohio State University, Columbus; University of Minnesota, Minneapolis and Hadassah University, Jerusalem, Israel.

As each university joins the National Blood-Brain Barrier Program, extensive meetings are held with clinicians involved in the program. Each university sends a team of individuals, including a clinical nurse coordinator who will be coordinating the BBBD procedure and managing patient care, to OHSU for a week of training. The training visit includes learning the BBBD procedure, patient management before and after the BBBD procedure, chemotherapy protocols used in conjunction with BBBD and use of standardized data collection instruments. The clinical nurse coordinator plays a vital role in both the synchrony of the disruption procedure and the coordination of all aspects of patient care.

On a weekly basis, the coordinating center reviews radiographic studies sent by the participating universities on patients who may be candidates for blood-brain barrier disruption treatment. The patients' past medical history, information regarding previous radiation or chemotherapy, current neurological and current functional status are also reviewed. The coordinating center advises and consults as necessary regarding ongoing management of patients enrolled in the National Program.

In addition, OHSU as the coordinating center shares results of pre-clinical and clinical research with the National Program participating centers as they become available. The OHSU Blood-Brain Barrier team also coordinates multi-institutional clinical grants and assumes primary responsibility for developing chemotherapy protocols, data collection instruments and quality assurance measures for use at all institutions. The National Program database is maintained at OHSU. The coordinating center also organizes an annual National Blood-Brain Barrier Program meeting, which is attended by all participating university program directors and clinical nurse coordinators. The annual meeting provides an opportunity for each university to present an update of their program's progress and to discuss protocols as well as future directions of blood-brain barrier therapy.

Patient Eligibility for Blood-Brain Barrier Disruption

Malignant brain tumors treated in the National Blood-Brain Barrier Program include high and low grade glioma, primitive neuroectodermal tumor (PNET), germ cell tumors, CNS lymphoma and metastatic cancer to the brain. Patients who are immunologically compromised or who have radiographic signs of CNS herniation are ineligible for this treatment. Because the technique involves general anesthesia, the patient's baseline cardiopulmonary status is key to a well-tolerated procedure. Patients at significant increased risk for general anesthesia are ineligible for BBBD, as are patients with prior vascular surgery such as femoral artery grafting or carotid endarterectomy. In addition, patients must have normal renal function and an Eastern Cooperative Oncology Group (ECOG) score less than or equal to 2 (Karnofsky Performance Status [is greater than or equal to] 60%). Written informed consent is obtained from each patient in accordance with institutional regulations.

Patients are admitted to the hospital once a month for two consecutive days of treatment. Twenty-four treatments are administered over approximately 12 months. The BBBD procedure itself and the associated patient care are managed by a multidisciplinary team.

Blood-Brain Barrier Team

The Blood-Brain Barrier team includes clinical nurse coordinators, neurosurgeons, neuroradiologists, anesthesiologists, hematologist-oncologists, medical psychologists, ophthalmologists, pharmacists, social workers and administrative assistants. The role of each team member includes:

* Clinical nurse coordinator (advanced practice nurse): coordinates the BBBD procedure and manages all aspects of patient care, including monthly hospital admissions of the patients as well as follow-up care necessary between monthly admissions.

* Neurosurgeon: oversees all aspects of BBBD program including all BBBD procedures and directs patient care.

* Neuroradiologist: conducts angiographic procedure including cannulation of the femoral artery, interprets radiographic studies to assess tumor response to treatment.

* Anesthesiologist: conducts preoperative assessment of patient at baseline and monthly, administers general anesthesia during BBBD procedure.

* Hematologist-oncologist: evaluates and manages patient's hematologic and renal tolerance of high-dose chemotherapy.

* Medical psychologist: conducts medical-psychological testing of patients at entry into BBBD program and at follow-up.

* Ophthalmologist: conducts baseline and follow-up ophthalmologic evaluation.

* Pharmacist: consults with clinical nurse coordinator and neurosurgeon regarding doses, administration and possible adverse effects of chemotherapy.

* Social worker: acts as resource for patient's transition from hospital to home including financial issues, physical therapy and patient/family psychological and social support.

* Administrative assistant: schedules monthly hospital admissions for patients as well as pre-admission tests.

The Blood-Brain Barrier Disruption Procedure

The blood-brain barrier disruption procedure is performed in either an operating room suite or an angiography suite and involves general anesthesia. The general anesthesia ensures patient comfort, and since focal motor seizures occur during approximately 7% of BBBD procedures, provides the capability of rapid control of seizure activity if necessary. An indwelling urinary catheter is placed to closely monitor fluid balance. Intravenous chemotherapy is begun as soon as the patient is under anesthesia. It is desirable for the intravenous chemotherapy to be delivered prior to osmotic opening of the blood-brain barrier, to allow time for the respective agents to be metabolized and delivered to tumor while the barrier is open. A femoral artery is catheterized and a selected intracranial artery (either an internal carotid or vertebral) is accessed. Catheter placement in the appropriate artery and catheter level is confirmed via fluoroscopy. Mannitol (25%) is then delivered via an infusion device at a predetermined rate of 3-12 cc per second for a 30 second period. The hyperosmolar mannitol solution osmotically opens the blood-brain barrier. Following the administration of mannitol and opening of the barrier, intraarterial chemotherapy is then administered, also by infusion device. The intraarterial agents are administered over 10 minutes in a predetermined volume.

Immediately following the disruption, non-ionic contrast dye is administered intravenously. Following completion of intravenous and intraarterial chemotherapy, the patient is transported under general anesthesia for a computed tomography (CT) scan. Since the barrier opening is transient, it is essential that a CT scan be obtained as soon as possible and no later than one hour following the disruption so the degree of disruption can be determined and documented (Figs 2A, 2B). It is important that a good degree of disruption be obtained, since the better the disruption, the better the chemotherapy delivery across the barrier. After the CT scan is completed, the patient is transported to the postanesthesia care unit for extubation and monitoring.

[Figure 2 ILLUSTRATION OMITTED]

Chemotherapy Protocols

The goal of BBBD is to maximize drug delivery. By administering chemotherapy in conjunction with osmotic opening of the blood-brain barrier, drug delivery can be increased 10 to 100-fold. Administration of intraarterial chemotherapy is also desirable since drug delivery is maximized via this route. The preclinical and clinical research groups at OHSU are constantly involved in toxicity studies to determine which chemotherapy agents can safely be delivered across the blood-brain barrier. Intensive pre-clinical laboratory animal studies are conducted prior to clinical studies involving patients. All studies involve dose escalation to determine the maximum tolerated dose. As soon as a safely tolerated dose of the agent under study is identified, it is placed into a multi-drug protocol. For example, we recently completed a clinical phase I toxicity study of etoposide phosphate. This agent is the phosphorylated form of etoposide and can be administered intraarterially. Etoposide phosphate is being used in our tri-drug protocols.

The chemotherapy protocols used in conjunction with BBBD involve both intraarterial and intravenous chemotherapy. There are currently three protocols in use in the National Program. The chemotherapy protocols are:

* intraarterial methotrexate, intravenous etoposide phosphate, and intravenous cyclophospamide (Cytoxan)

* intraarterial carboplatin, intravenous etoposide phosphate, and intravenous cyclophosphamide

* intraarterial methotrexate and intravenous cyclophosphamide.

In these regimens methotrexate and carboplatin are administered intraarterially; however Cytoxan requires hepatic activation and therefore is administered intravenously. Granulocyte colony stimulating factor (Neupogen) is given to patients following each course of BBBD, starting 48 hours after the last dose of chemotherapy. The purpose of this is to reduce the duration of neutropenia following chemotherapy administration, and to maintain a low incidence of neutropenia-related infections as manifested by febrile neutropenia. The dose of Neupogen is either 300 mcg or 480 mcg (5 mcg/kg) depending on the patient's body weight, administered subcutaneously each day for 7-10 days. In addition, patients who receive methotrexate also receive leucovorin rescue 36 hours following the first methotrexate infusion. The patients are given leucovorin 80 mg intravenous once and then 50 mg orally every six hours for 20 doses (five days) following BBBD treatment.

Patients with CNS lymphoma are treated with the methotrexate, etoposide phosphate and cytoxan regimen. Patients with PNET, germ cell, glioma and metastatic cancer receive carboplatin, etoposide phosphate and Cytoxan. The third protocol is methotrexate and Cytoxan. This regimen is used in patients enrolled in our Phase III randomized glioma trial. Patients with high-grade glioma are eligible for this trial, and are randomized into one of two arms. In arm I, patients receive radiation therapy followed by chemotherapy + BBBD; in arm II, patients receive chemotherapy + BBBD followed by radiation therapy.

Nursing Care of Patients Undergoing BBBD

Preparation and Teaching

Patients are initially seen in the out-patient clinic. If the patient meets eligibility criteria, the clinical nurse coordinators explain the details of the BBBD procedure, monthly hospitalizations, follow-up testing, risks and potential adverse effects of BBBD and chemotherapy, to patients and their significant others. Once the patient chooses to enter the program, he/she is closely followed by the BBB nurse coordinators and fellows.

Admission Work-up and Studies

Patients are admitted to the hospital the afternoon preceding the first BBBD treatment since numerous interventions are necessary prior to undergoing the disruption procedure. A history and physical examination by a BBB nurse coordinator is performed. A battery of laboratory blood tests including complete blood count (CBC), creatinine, electrolytes, clotting times and liver enzymes is done. Antiepileptic drug (AED) levels are obtained on patients who are maintained on AEDs. A CT scan, chest xray and urinalysis are obtained. In addition, neuropsychological testing is done on admission to the program. A monthly audiogram is also done for patients receiving carboplatin-based chemotherapy. A monthly electrocardiogram (ECG) is done in patients over the age of 40 years, or if clinically indicated. A central venous access device is placed early in the program because of the frequent need for intravenous access. Intravenous fluids are started so that the patient is well hydrated prior to the BBBD procedure and the infusion of chemotherapy. Patients receiving the methotrexate-based regimen also receive sodium bicarbonate as part of their intravenous hydration, to alkalinize the urine.

Test results are carefully analyzed prior to treatment with BBBD. The CT scan is reviewed by the entire team to evaluate the safety of BBBD. Patients with increased intracranial pressure as evidenced by ventricular shift or compression of the quadrigeminal plate are not eligible for BBBD. The patient's neurological status is closely monitored, both as a baseline and for immediate detection of any changes which might have occurred in the patient's neurological status. Changes of most concern include those indicative of increased intracranial pressure. Changes in vital signs are also promptly noted. If the patient has an elevated temperature indicating an underlying infection, the BBBD procedure is cancelled.

Fluid and Electrolyte Balance

During the BBBD procedure, the patient receives a large dose of intraarterial mannitol. There is a 1.5% increase in brain water associated with the procedure. A large volume of chemotherapy is also administered. In addition, the anesthesiologist typically has an intravenous line of normal saline infusing. Because of the above agents and fluids, we frequently see large fluctuations in fluid and electrolyte status. Meticulous intake and output record-keeping is essential during and after the BBBD procedure. The clinical nurse coordinator oversees the BBBD procedure and is responsible for maintaining accurate records of all fluids administered to the patient during the procedure, as well as urine output. A running total is begun during the first BBBD procedure, and is maintained during the following 48 hours. The goal is to maintain the patient's fluid balance between matched intake and output, and 500 cc "positive" fluid balance. If the patient develops a negative fluid balance then replacement boluses are ordered. If the patient develops a positive balance greater than 500 cc then an appropriate diuretic is ordered. Furosemide cannot be used in conjunction with carboplatin, because of the ototoxic adverse effect.[22] In this case, intravenous mannitol may be ordered to assist with diuresis. Clearly, fluid balance concerns are two-fold; 1) it is very important that the patient does not evolve into a highly "positive" fluid balance because of the risk of increasing intracranial pressure as well as stressing cardiopulmonary function; and 2) because of the large doses of chemotherapy the patient receives during the BBBD procedure, a highly "negative" fluid balance may lead to chemotherapy toxicities such as renal failure.

Weekly Follow-up Between Monthly Admissions

Laboratory studies are ordered on all patients following hospital discharge. This is particularly important in view of the myelosuppressive effect of chemotherapy. In order to closely monitor patient's white blood cell (WBC) counts, the incidence and duration of neutropenia and to quickly identify any evidence of neutropenia-related infections, a complete blood count (CBC) is ordered once a week (twice a week during the immediate post-procedure period when the patient is taking Neupogen). A urinalysis is ordered once a week. In addition the patient monitors his/her temperature each day to detect any sign of possible infection. The clinical nurse coordinators are in contact with patients on a weekly basis by telephone. The frequency of calls from the clinical coordinators is increased while the patient is taking Neupogen and/or leucovorin to ensure patient compliance and provide guidance as needed regarding these medications. Home health care or supervision is ordered as necessary and a clinical social worker oversees the coordination of out-patient agencies and therapies. Depending on the patient's neurological and functional status, physical and occupational therapy may be required.

Potential Adverse Effects and Risks

There are risks related to BBBD treatment. Analysis of complications that occurred in the last 37 patients treated with the carboplatin, cytoxan and etoposide protocol showed that six patients developed deep vein thrombosis. Transient neurological deficits such as unilateral motor weakness or expressive aphasia may occur immediately following the procedure. These deficits are treated with intravenous dexamethasone and resolve within 24-48 hours after BBBD. Seizures are associated with 7% of procedures. These are usually focal in nature and occur during the procedure when the patient is under general anesthesia. Patients receive preoperative diazepam and those noted to have a predisposition to seizures may additionally be medicated immediately prior to the procedure with lorazepam. Intraprocedural seizures are controlled with a barbiturate (thiopental) frequently used in conjunction with BBBD anesthesia. Patients receive ondansetron (Zofran) to prevent post-procedure nausea. Additional risks include stroke occurring in .25% of BBBD procedures. Obtundation lasting greater than 24 hours has occurred infrequently in .3% of procedures. Adverse events are closely tracked with data collection instruments and the information obtained is used to guide and improve clinical management. There has been one procedurally-related death at OHSU in over 3000 procedures.

An unexpected complication secondary to our use of carboplatin in conjunction with BBBD has been high-frequency hearing loss. This complication has occurred in approximately 79% of patients receiving carboplatin, often necessitating changing the patient's chemotherapy protocol to prevent further hearing loss. As a result we instituted sodium thiosulfate as an agent to reduce the ototoxicity of carboplatin. The sodium thiosulfate results are further discussed under "future directions."

Results of BBBD therapy

Non-Aids Primary CNS Lymphoma

The most recent CNS lymphoma report from the OHSU program includes 58 patients with CNS lymphoma treated with BBBD chemotherapy using methotrexate, cytoxan, procarbazine and dexamethasone.[8] The patients were treated at OHSU between January 1982 and March 1992. Group 1 patients (n=19) were initially treated with cranial radiation and subsequently received BBBD chemotherapy. Group 2 patients (n=39) received initial BBBD chemotherapy only, following diagnosis.

There was no significant difference in patient characteristics between Group 1 and Group 2. Tumor response was assessed radiographically by measuring the change in the estimated volume of the contrast-enhancing lesion on CT scan obtained at baseline and prior to each treatment. A complete response was recorded if there was no tumor enhancement on contrast CT, and negative cytology. A partial response was defined as [is greater than or equal to] 50% reduction in enhancing tumor volume. In 15 evaluable Group 1 patients, 14 demonstrated objective response and 7 of 14 (50%) achieved a complete response. In Group 2, 34 of 35 evaluable patients demonstrated objective response, with 29 complete responses. The estimated median survival time for Group 1 patients was 16 months and for Group 2 patients was 41 months. Extensive neuropsychological follow-up (up to 7 years) was completed in 23 patients and demonstrated preserved or improved cognitive function. As of May, 1996, 19 Group 2 patients and 2 Group 1 patients were alive. This data is the first example of such a prolonged response in a primary brain tumor using enhanced chemotherapy delivery without radiotherapy, and thus without the neurologic sequelae so often associated with radiation.[8]

Case Study: CNS Lymphoma

A 25 year-old male patient presented with a two week history of frontal headaches and focal seizures. A magnetic resonance imaging (MRI) scan revealed an enhancing intracranial mass. The patient underwent a partial surgical resection, and pathology revealed CNS lymphoma. The patient underwent BBBD plus methotrexate tri-drug chemotherapy regimen beginning March, 1993. The following month the patient was hospitalized with febrile neutropenia. The patient proceeded through five more months of BBBD without complications. An additional hospitalization for febrile neutropenia followed six months of treatment. The patient then successfully completed a year of BBBD treatment. Three years following diagnosis, the patient married, graduated from law school and successfully passed the bar exam. He is currently practicing law four years after diagnosis.

PNET

Allen et al reported the high sensitivity of medulloblastoma to carboplatin.[2] A carboplatin-based regimen (carboplatin and etoposide) was implemented at OHSU in 1991 and has been determined to be an effective regimen for the treatment of PNET. Cytoxan was added to the regimen in 1993. Of the 16 patients with PNET who have been treated with BBBD plus carboplatin-based chemotherapy, 11 (62%) had an objective radiographic response including nine complete responses and two partial responses.[9] There are currently nine patients alive (6-64 months from diagnosis and 5.5-33 months from initiation of BBBD treatment). These include two patients who received no radiation, two with prior radiation and five who had radiation following the BBBD treatment. Of these nine patients, three remain in complete response, three have stable disease and three have recurrent disease.

It is evident that PNETs respond initially to carboplatin-based chemotherapy with BBBD. However, it is also evident that consolidation with radiation therapy is needed. We are currently developing a consolidation regimen which includes post-BBBD radiation. Our goal is to minimize cognitive sequelae secondary to radiation therapy, while continuing to recognize the importance of radiation therapy to ensure a durable remission.

Case Study: Pineoblastoma

A twenty-seven year-old male patient presented with a five month history of headaches, blurred vision, dizziness and fatigue. An MRI revealed an enhancing lesion in the pineal region. A biopsy revealed pineoblastoma. There was no evidence of drop metastases. The patient began BBBD therapy in June, 1994. Following the first course of treatment, there was a complete objective radiographic response on CT. The patient completed 24 BBBD treatments over the course of one year without complications or significant delays. He then underwent focal radiation (5400 cGy) to the pineal region. At last follow-up, three years post diagnosis, head and spine MRI show no evidence of disease.

Glioma

Radiation therapy has proven to be an effective adjunct to surgery in improving survival for patients with malignant glioma. Historically, chemotherapy is routinely administered following radiotherapy. However, such a sequencing regimen (chemotherapy subsequent to cranial radiation) may obscure the benefit of initial administration of chemotherapy.[19] Thus, our interest is in studying the effects of sequencing radiation therapy and blood-brain barrier chemotherapy on survival time and cognitive function.[15,21]

Chemotherapy with BBBD after Radiotherapy

The OHSU series includes 57 patients with malignant glioma. All received cranial radiation prior to referral for combination chemotherapy (initial intraarterial methotrexate based [n=53] or intraarterial carboplatin based [n=4]) in conjunction with BBBD. Mean patient age was 43 years and mean Karnofsky score was 82% on inclusion in the protocol. All underwent extensive neuropsychological evaluation. Statistical analysis (Kaplan Meier and log-rank) evaluated estimated median survival and prognostic variables (age, Karnofsky status, tumor necrosis at diagnosis). The estimated median survival was 17 months. The only variable that had a statistically significant correlation with survival was Karnofsky performance status.

Gumerlock and colleagues have obtained and published similar results.[12] Their use of osmotic BBB modification to enhance drug delivery to tumor and surrounding brain resulted in a survival advantage over conventional therapy. In a series of 37 patients undergoing 246 treatment procedures of combination chemotherapy (methotrexate, cytoxan and procarbazine) and osmotic BBBD, the estimated median survival was 22 months and the median Karnofsky performance status on admission of 67% increased to 75% after six treatments.

Chemotherapy with BBBD before Radiotherapy

Twenty-one patients are included in the OHSU series. Postoperative combination chemotherapy has consisted of an initial intraarterial methotrexate (n= 16) or intraarterial carboplatin-based (n = 5) combination chemotherapy regimen with BBBD. Only 8 of the 21 patients received subsequent cranial radiation and this was delayed until recurrence. Patients ranged in age from 17-68 years (mean = 46) and had Karnofsky scores of 40-100% (mean = 87%) on inclusion in the protocol. Although 13 (62%) of these patients did not receive radiation and the other 8 received radiation at recurrence, these patients had an estimated median survival (Kaplan-Meier analyses) of 17 months from diagnosis. Prognostic factors evaluated included age at diagnosis, Karnofsky performance status and presence of necrosis at diagnosis. In this series, only performance status clearly correlated with survival. All patients underwent extensive neuropsychologic evaluation on inclusion in the protocol and at completion of the protocol if there was no evidence of progressive disease. Of four patients who were complete responders for 14-40 months and who underwent such serial evaluations, there was no evidence of cognitive decline. Progression-free interval in these patients ranged from 1-40 months at the end of data collection with ongoing long-term follow-up.

There was no statistically significant difference in estimated median survival between patients in these two series who underwent postoperative cranial radiation followed by combination chemotherapy with BBBD or postoperative combination chemotherapy with BBBD. These results are of particular importance in light of the fact that survival times from diagnosis (17 months) are parallel despite the fact that only 8 of the patients who received initial postoperative combination chemotherapy subsequently received cranial radiation.

Neuropsychological Outcome

A major ongoing focus of the clinical blood-brain barrier program at OHSU has not only been length of survival, but quality of survival. A combination of global cognitive deficits and emotional instability have been documented as primary neurobehavioral manifestations related to radiation treatment.[6] Toxicity from radiation can have marked adverse effects on patients' quality of life during the time of their survival. A comprehensive review of world-wide studies over a ten-year period has shown that both traditional and newer forms of radiation therapy carry the risk of reducing overall cognitive function.[7] For patients successfully treated with BBBD plus chemotherapy, the treatment approach has been shown to preserve cognitive function in children, young adults and adults over 60 years old. In the population of CNS lymphoma patients reported by Dahlborg, extensive neuropsychological follow-up documented preservation or improvement in cognitive function in patients receiving initial BBBD chemotherapy.[8]

Future Directions

Carboplatin-Induced Ototoxicity

Sodium thiosulfate is used clinically as an antidote for cyanide poisoning and nitroprusside overdose.[4] When used for cyanide poisoning, the dose of sodium thiosulfate is 12.5 grams given intravenously over approximately 10 minutes. Following intravenous injection, sodium thiosulfate is distributed throughout the extracellular fluid and is excreted unchanged in the urine, with a biological half-life reported to be 0.65 hours.[3] There are no known adverse reactions or contraindications when used as an antidote. Sodium thiosulfate has been shown to be a useful chemoprotectant when used in conjunction with cisplatin. Treatment with sodium thiosulfate can prevent cisplatin toxicity in vitro[1] and reduces cisplatin nephrotoxicity in animal models.[13] We have demonstrated that sodium thiosulfate protects against carboplatin-induced ototoxicity.[17]

In order to test sodium thiosulfate as a chemoprotective agent against carboplatin-induced ototoxicity, we administered this agent to patients undergoing BBBD in conjunction with the carboplatin, cytoxan and etoposide regimen. The study began in May, 1995. We initially administered sodium thiosulfate two hours following intraarterial carboplatin infusion as a 4 g/[m.sup.2] intravenous bolus over 15 minutes, followed by a six-hour slow infusion of 12 g/[m.sup.2]. We monitored vital signs, serum electrolytes and arterial blood gases as well as plasma and urine levels of sodium thiosulfate. We noted mild and transient nausea and vomiting in a small number of patients. There were no other adverse effects. We then escalated the dose to 8 g/[m.sup.2], and administered this dose as an intravenous bolus over 15 minutes, two hours following the intraarterial carboplatin, to three patients. Vital signs, arterial blood gases, serum electrolytes and plasma and urine sodium thiosulfate levels were obtained at baseline immediately after bolus infusion and every 15 minutes thereafter for 30 minutes. We continued to escalate the sodium thiosulfate dose to 12, 16 and 20 gr/[m.sup.2]. At least three patients received a dose at each level before any patient was escalated to the next level. At all dose levels, patients had monthly audiograms. At 20 g/[m.sup.2], transient serum sodium increase of 10-15% was noted in all patients receiving that dose. A transient increase in blood pressure (10-15%) accompanied the hypernatremia.

We have shown a clear difference in the hearing of patients treated with sodium thiosulfate versus a historical comparison group of patients not treated with sodium thiosulfate. The incidence of ototoxicity in the historical comparison group was 79%. Patients in this group had an average loss of 20.8 [+ or -] 5.9 dB (n= 19) at 8 KHz after one treatment with carboplatin, while the group treated with a high dose sodium thiosulfate (16 or 20 g/[m.sup.2]) lost only 3.7 [+ or -] 2 dB (n = 15) after one treatment. Our plan is to further determine the optimal dose and timing of sodium thiosulfate administration.[17]

Intraarterial Chemotherapeutic Agents

Intraarterial administration of chemotherapeutic agents has been shown to increase drug delivery to brain over intravenous administration when used in conjunction with BBBD.[16] Since intraarterial administration maximizes delivery to tumor mass, a major focus in the OHSU BBB laboratory has been to identify alternative agents that can safely be administered intraarterially, in conjunction with BBBD. For example, etoposide phosphate, the phosphorylated form of etoposide, permits administration of increased concentrations of the drug systemically and also permits intraarterial administration. Etoposide phosphate is one of a large series of etoposide derivatives prepared in an attempt to improve the characteristics of the parent compound. The advantage of etoposide phosphate is its water solubility: this makes it easier to formulate and administer than etoposide. It also has a very rapid in vivo conversion to etoposide, which gives it the same therapeutic characteristics as the parent compound.

Etoposide phosphate has replaced intravenous etoposide in our tri-drug chemotherapy protocols. Next we plan to begin a phase I clinical study with melphalan, an alkylating agent that has been found safe for intrathecal and intracarotid administration in preclinical studies,[10,14] with the hope of replacing intravenous cytoxan with intraarterial melphalan in our tri-drug protocols.

Gene Therapy

BBBD is not only important in the treatment of brain tumors, but also as a means to deliver other agents to the brain, for example in neurodegenerative diseases. Our laboratory studies are aimed toward delivery of therapeutic genes to diseased brain. For example, in Parkinson's disease the symptoms are due to progressive loss of the dopamine neurons. The OHSU blood-brain barrier preclinical team will attempt to replace the function of the dopaminergic neurons by transferring important genes in the dopamine pathway to other brain cells. Although replacement of a single gene will not "cure" the disease, single genes may be useful for therapy. Also, transfer of a gene for a neurotropic factor to patients with Parkinson's disease or after stroke, may have a role in reducing neuronal cell death and may stop the progression of neurologic symptoms. Gene therapy studies have begun in a rat model of Parkinson's disease. The preclinical lab is testing the hypothesis that the BBBD delivery of viral vectors will increase the delivery and the efficacy of therapeutic genes.

Summary

As an exciting new frontier, BBBD optimizes drug delivery to tumor, and also provides a technique for administering new agents such as immunotoxins and gene therapy across the blood-brain barrier for the treatment of numerous central nervous system diseases. Advanced practice nurses play a vital role in the coordination of the BBBD procedure, as well as in the comprehensive management of patients during their treatment course and at follow-up.

Acknowledgements

The authors wish to dedicate this manuscript to the late Suellen A. Dahlborg RN, JD, in honor of her commitment and devotion to the Blood-Brain Barrier Program and the care of patients with malignant brain tumors. Ms. Dahlborg coordinated the establishment of the National Blood-Brain Barrier Program. We also thank Dr. Edward A. Neuwelt for sharing his expertise and pioneering work regarding the blood-brain barrier, as well as for his unswerving support and value of the many nurses involved in the National Program. In addition, we are grateful to Gail Engles for editorial assistance, and to Raylene Coleman, ANP, Rose Marie Tyson, ANP and Cindy Lacy, RN, for ongoing clinical consultation.

References

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[2.] Allen JC, Walker R, Luks E: Carboplatin and recurrent childhood brain tumors. J Clin Oncol 1987; 5:459-463.

[3.] American Regent Product Information, 1992.

[4.] Baskin SI, Horowitz AM, Nealley EW: The antidotal action of sodium nitrite and sodium thiosulfate against cyanide poisoning. J Clin Pharmacol 1992; 32:368-375.

[5.] Carpenter MB: Pages 14-20 in: Core Text of Neuroanatomy 4th ed. Williams & Wilkins, 1991.

[6.] Crossen JR, Goldman DL, Dahlborg SA, Neuwelt EA: Neuropsychological assessment outcomes of non-Aids primary central nervous system lymphoma patients before and after blood-brain barrier disruption chemotherapy. Neurosurgery 1992; 30:23-29.

[7.] Crossen JR, Garwood A, Glatstein E, Neuwelt EA: Neurobehavioral sequelae of cranial irradiation in adults: A review of radiation induced encephalopathy. J Clin Oncol 1994; 12:627-642.

[8.] Dahlborg SA, Neuwelt EA, Henner WD, Crossen JR, Tableman M, Petrillo A: Non-Aids primary CNS lymphoma: The first example of durable response in a brain tumor using enhanced chemotherapy delivery without cognitive loss and without radiotherapy. Cancer J Sci Am 1996; 2:166-174.

[9.] Dahlborg SA, Petrillo A, Crossen JR, Roman-Goldstein S, Doolittle ND, Fuller KH, Neuwelt EA: The potential for complete and durable response in non-glial primary brain tumors in pediatric patients and young adults with enhanced chemotherapy delivery. Cancer J Sci Am 1998; 4:110-124.

[10.] Friedman HS, Archer GE, Mc Lendon RE, Schuster JM, Colvin OM, Guaspari A, Blum R, Savina PA, Fuchs HE, Bigner DD: Intrathecal melphalan therapy of human neoplastic meningitis in athymic nude rats. Cancer Res 1994; 54:4710-4714.

[11.] Gumerlock MK: Principles of chemotherapy in brain neoplasia. Pages 277-348 in: Therapy of Malignant Brain Tumors, Jellinger K (editor). Springer-Verlag, 1987.

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Question or comments about this article may be directed to: Nancy D. Doolittle, RN, PhD, Assistant Professor, Department of Neurology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road - L603, Portland, Oregon 97201.

She is the national coordinator, Blood-Brain Barrier Program. Annie Petrillo, RN, ANP, is clinical coordinator, Blood-Brain Barrier Program, Oregon Health Sciences University, Portland. Oregon.

Susan Bell, RN, MS, CNR, CS, is clinical coordinator, Blood-Brain Barrier Program, Ohio State University, Columbus, Ohio Pamela Cummings, RN, MS, is clinical coordinator, Blood-Brian Barrier Program, Trinity Lutheran Hospital, Kansas City, Missouri.

Sharon Eriksen, RN, CNRN, is clinical coordinator, Blood-Brain Barrier Program, University of Minnesota, Minneapolis, Minnesota.
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Author:Doolittle, Nancy D.; Petrillo, Annie; Bell, Susan; Cummings, Pamela; Eriksen, Sharon
Publication:Journal of Neuroscience Nursing
Date:Apr 1, 1998
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