Blood-Brain Barrier Disruption Chemotherapy

Chapter 10

Blood-Brain Barrier Disruption Chemotherapy John M. McGregor*, Susan D. Bell*, Nancy D. Doolittle†, Tulio P. Murillo‡, and Edward A. Neuwelt†,§ *Department of Neurological Surgery, The Ohio State University, Columbus, OH, United States, † Department of Neurology, Oregon Health and Science University, Portland, OR, United States, ‡ Department of Neurosurgery, Honduras Medical Center, Tegucigalpa, Honduras, § Department of Neurosurgery, Oregon Health and Science University, Portland, OR, United States

INTRODUCTION The efficacy of chemotherapy for malignant brain tumors has in general been disappointing, in part due to the limited passage of many systemically administered agents from the blood to the brain. The blood-brain barrier (BBB) excludes molecules from the brain based on the electric charge, lipid solubility, and molecular weight. Molecules of greater than Mr180 are typically excluded. Investigators have previously reported the variability in brain tumor permeability within malignant brain tumors, and that the well-vascularized, actively proliferating edge of the tumor is particularly variable in terms of barrier integrity [1–3]. The current BBB transport paradigm is that movement across the BBB relates to the neurovascular unit, which consists of endothelial cells, pericytes, glia, and neuronal elements [4,5]. The goal of blood-brain barrier disruption (BBBD) is maximizing the delivery of agents to the brain while preserving the neurocognitive function and quality of life, and minimizing systemic toxicity. BBBD is especially important in increasing the delivery of high molecular weight agents such as proteins, antibodies, immunoconjugates, and viral vectors [4,6]. BBBD involves administering the hyperosmolar solution mannitol intraarterially in the carotid or vertebral arteries. The infusion of mannitol is theorized to cause osmotic shrinkage of endothelial cells which line the central nervous system (CNS) capillaries, with resultant separation of the tight junctions between the cells. Cellular messenger systems such as calcium influx and nitrous oxide, as well as cytoskeletal changes, likely contribute to the transient opening of the barrier. To date, BBBD has shown promising clinical results in chemosensitive brain tumors such as the primary central nervous system lymphoma (PCNSL). Translational studies conducted in the laboratory and in the clinic have led to innovative approaches such as a twocompartment BBB model, which is an exciting paradigm involving temporary and reversible osmotic opening of

the BBB (see Fig. 10.1A and B). The two-compartment model is based on separating platinum chemotherapy and thiol chemoprotectants, by route and by timing of administration.

PRECLINICAL BBB DELIVERY STUDIES Many important BBBD observations have been made in animal studies. For example, (1) a marked increase in brain and cerebrospinal (CSF) concentrations of methotrexate were documented after BBBD with intraarterial chemotherapy administration [7–9]; (2) disruption of the BBB provides global delivery throughout the disrupted hemisphere, but is variable depending on the brain region and the type and size of the tumor; (3) vascular permeability to small molecules such as methotrexate, as well as large molecules such as mAbs, is increased maximally by 15 min after mannitol; and (4) BBB permeability rapidly decreases, returning to preinfusion levels within 2 hours after BBBD. Animal studies have also shown that antecedent cranial irradiation decreases agent delivery to the brain [10,11]. The studies evaluated long-term effects of various sequences of radiation therapy and BBBD chemotherapy in rodents. Drug delivery, acute toxicity, and long-term (1 year) neuropathological effects of methotrexate, or carboplatin plus etoposide, were evaluated. External beam radiation of 2000 cGy as a single fraction using parallel-opposed portals, either 30 days before or concurrent with BBBD, resulted in a statistically significant decrease in drug delivery compared with animals not receiving cranial irradiation. Seizures were observed in 26% of the animals that received irradiation before or concurrent with BBBD and methotrexate, but not carboplatin. The mortality rate for animals receiving radiotherapy 30 days before chemotherapy was significantly higher than the mortality rate for animals receiving only BBBD chemotherapy without irradiation [10,12].

Handbook of Brain Tumor Chemotherapy, Molecular Therapeutics, and Immunotherapy. https://doi.org/10.1016/B978-0-12-812100-9.00010-3 Copyright © 2018 Elsevier Inc. All rights reserved.

145

146

SECTION

II Innovative Chemotherapy Delivery

FIG. 10.1 The two-compartment model. Carboplatin (carbo) is administered intraarterially immediately after osmotic disruption of the BBB with hypertonic mannitol: (A) delivery of carboplatin across the BBB. STS is administered intravenously 4 (or 4 and 8) hours after osmotic disruption, after BBB permeability has returned to baseline levels and (B) exclusion of STS from the brain.

Brain

BBB

Blood

Brain

carbo

BBB

carbo

carbo carbo

carbo

carbo carbo

carbo

carbo

carbo

(A)

Additional rodent studies evaluated whether prior irradiation influenced the efficacy of antibody-targeted chemotherapy given with BBBD. Results have shown that BR96-DOX, an antitumor mAb-doxorubicin immunoconjugate, administered before irradiation significantly increased survival compared with rodents receiving irradiation before chemotherapy, or compared with those receiving chemotherapy concurrently [11]. These findings were later supported in the clinic when subjects with PCNSL, who received cranial irradiation before beginning BBBD chemotherapy, had significantly decreased median survival time compared with subjects who received initial BBBD chemotherapy [13]. The BBB preclinical and clinical teams carefully conduct toxicity studies, in animals and in humans, respectively, to determine which chemotherapy agents can be administered with BBBD with an acceptable safety and toxicity profile. However, extensive preclinical toxicity studies are always conducted before phase 1 clinical studies. For example, important knowledge was gained when laboratory studies showed severe neurotoxicity when adriamycin (intraarterial) [14], cisplatinum (intraarterial), or 5-FU (intraarterial) [15] were administered as single agents after BBBD. Fortin [16] reported unexpected neurotoxicity when etoposide phosphate (intraarterial) was administered in combination with melphalan (intraarterial), methotrexate (intraarterial), or carboplatin (intraarterial) after BBBD, when propofol anesthesia was used. Chemotherapy agents used most frequently in conjunction with BBBD in the clinical setting are methotrexate (intraarterial, 2500 mg/day
2 consecutive days), carboplatin (intraarterial, 200 mg/m2/day
2 consecutive days), melphalan (intraarterial, a dose of 6 mg/m2/day
2

carbo

carbo

carbo

STS carbo STS

carbo

carbo

carbo STS

carbo

carbo

Blood

carbo carbo

STS carbo STS STS

(B)

consecutive days), cyclophosphamide (intravenous, 500 mg/m2/day
2 consecutive days when given with methotrexate; 330 mg/m2/day
2 consecutive days when given with carboplatin), etoposide and etoposide phosphate (intravenous, 150 mg/m2/day
2 consecutive days when given with methotrexate; 200 mg/m2/day
2 consecutive days when given with carboplatin). Depending on the brain tumor histology and according to the specific IRB-approved protocol, a combination of the above drugs is given with BBBD. These agents infused by the respective routes and doses have been routinely used in the clinical setting and have shown acceptable toxicity [13,17–20].

CLINICAL BBBD TECHNIQUE The care of patients treated with BBBD requires a multidisciplinary team approach. The team includes a neurooncologist, neurosurgeon, neuroradiologist, anesthesiologist, pharmacist, nurse coordinator, neuropsychologist, ophthalmologist, audiologist, physical therapist, and social worker. BBBD treatment is done on 2 consecutive days every 4 weeks for up to 1 year. Patients undergo baseline neuropsychological evaluation, electrocardiogram, and port-a-cath placement. At baseline and prior to each monthly BBBD treatment patients undergo neurologic and Karnofsky Performance Scale (KPS) evaluation, brain magnetic resonance imaging (MRI), chest X-ray, complete blood count, chemistry panel, and urinalysis. Patients are required to have adequate hematologic, renal, and hepatic function, and must have adequate pulmonary and cardiac function to tolerate general anesthesia. Ophthalmologic assessment is done if clinically indicated. Patients treated

Blood-Brain Barrier Disruption Chemotherapy Chapter

with carboplatin in conjunction with BBBD undergo monthly audiologic assessment. In addition, all patients must meet neuroradiographic criteria before undergoing BBBD treatment. The radiographic criteria are: (1) an open quadrigeminal plate cistern, (2) absence of dilatation of the contralateral frontal horn, and (3) absence of uncal herniation. In the setting of rapidly progressing brain disease with associated rapid neurologic deterioration, there is a risk of increasing mass effect following BBBD, thus BBBD is safest before tumor burden becomes excessive [19]. BBBD is performed under general anesthesia to ensure patient comfort and safety during rapid intraarterial infusion of a large volume of hypertonic mannitol (25%, warmed). Focal motor seizures occur during approximately 7% of BBBD procedures (most often in conjunction with methotrexate); thus general anesthesia provides the capability of rapid control of seizures if necessary. A femoral artery is catheterized and a selected intracranial artery (either an internal carotid or a vertebral artery) is accessed. The transfemoral catheter is placed at cervical vertebrae 1–2 for a carotid artery infusion of chemotherapy or at cervical vertebrae 6–7 for a vertebral artery infusion. The transfemoral catheter placement level is confirmed by fluoroscopy before mannitol administration, and also before chemotherapy infusion. Mannitol is delivered via an infusion device at a predetermined flow rate of 3–12 cc per second into the cannulated artery for 30 s. The precise flow rate is determined by fluoroscopy, to just exceed the cerebral blood flow. Following administration of mannitol, the intraarterial chemotherapy agent(s) are infused, each over 10 min. If chemotherapy is administered via the intravenous route, it is begun as soon as the patient is under general anesthesia, to allow time for the chemotherapy to be delivered to the tumor while the barrier is open. If intraarterial

10

147

chemotherapy without BBBD is used, patients undergo monitored anesthesia care instead of general anesthesia, and treatment is on one day instead of 2 consecutive days every 4 weeks. Immediately following mannitol administration, nonionic contrast dye is administered intravenously. Following completion of chemotherapy, the patient undergoes a computed tomography (CT) brain scan (see Fig. 10.2A and B) [21]. Contrast enhancement in the disrupted territory of the brain is compared with the nondisrupted territory. The degree of disruption is graded using the results reported by Roman-Goldstein [22]. During each monthly treatment, one of the intracranial arteries (right or left internal carotid or a vertebral artery) is infused the first day of BBBD treatment, and a different artery is infused on the second day of BBBD, depending on the tumor type, extent, and location. In tumors that are not localized to one brain hemisphere or arterial territory, and/or tumors that have widespread microscopic infiltration of the brain such as PCNSL, infusion of the arteries is rotated so that during a year of BBBD treatment, each of the three intracranial arteries is infused eight times, thus providing global delivery to all cerebral circulations. Following BBBD and during their hospital stay, patients undergo close observation including frequent monitoring of vital signs, neurologic status, and fluid balance. Fluid balance is meticulously maintained with diuretics or fluid boluses. In patients treated with methotrexate, sodium bicarbonate is added to intravenous fluids and titrated to achieve a urine pH of greater than 6.5. Leucovorin rescue is used in methotrexate-based protocols, beginning 36 h after the first dose of methotrexate. Patients treated with methotrexate receive 80 mg of Leucovorin (intravenous) followed by 50 mg (intravenous or orally) every 6 h, for a total of 20 doses. Ganulocyte-colony stimulating factor (G-CSF) is given subcutaneously 48 h after the second FIG. 10.2 Computed tomographic (CT) images of BBBD of the left cerebral hemisphere following mannitol infusion in the left internal carotid artery (A), and BBBD of the posterior fossa region following mannitol infusion in the vertebral artery (B) [21]. Reprinted with permission from Doolittle ND, Petrillo A, Bell S, Cummings P, Eriksen S. Blood-brain barrier disruption for the treatment of malignant brain tumors: The National Program. J Neurosci Nurs 1998;30(2):80–91. Copyright 1998 by the American Association of Neuroscience Nurses.

(A)

(B)

148

SECTION

II Innovative Chemotherapy Delivery

day of BBBD chemotherapy. If filgrastim (Neupogen) is used, 5 μg/kg is given daily until the WBC is 5000/μL. If pegfilgrastim (Neulasta) is used, one dose of 6 mg is given. Following hospital discharge and between monthly BBBD treatments, complete blood counts are done twice a week for 2 weeks while the patient is receiving G-CSF. For the remaining 2 weeks, a complete blood count is done weekly. Patients treated with BBBD may experience transient neurologic deficits after the BBBD procedure. In the setting of a good or excellent disruption, approximately 10% of patients have decreased level of consciousness for up to 48 hours, and this may be accompanied by temporary aphasia and/or weakness of the upper or lower extremities. In these instances, patients are treated with dexamethasone, and usually return to baseline status within 48 h. The most common arterial injury that may occur during BBBD is a subintimal tear. These arterial injuries are usually asymptomatic and are noted during fluoroscopy of the carotid and vertebral arteries. If a subintimal tear occurs, mannitol and chemotherapy are not infused through the injured vessel, and the artery is reassessed with angiography 4 weeks later, before resuming intraarterial administration of mannitol or chemotherapy. There is a risk of deep venous thrombosis (DVT) in patients undergoing BBBD, thus patients routinely undergo Doppler monitoring of the extremities and those at high risk for DVT are placed on prophylactic anticoagulation therapy. Radiographic evidence of vascular injury, which may or may not be symptomatic, is seen in up to 5% of patients after BBBD [13,17–19]. In the event of a stroke, in most cases the patient is asymptomatic with brain MRI changes consistent with a small infarction. In patients with MRI changes and associated neurologic deficits, the deficits usually occur within 24 h after BBBD, may include speech impairment and/or unilateral extremity weakness, and are usually caused by a small embolus resulting from the arterial catheter placement and infusion. The neurologic deficits may last for greater than 48 hours; however, most patients return to baseline neurologic status within 30 days. Abnormal signal on cervical MRI has occurred in several patients treated with carboplatin-based chemotherapy with BBBD [23]. This toxicity requires immediate treatment with dexamethasone and very close observation of the patient. Carboplatin also causes high-frequency hearing loss when administered intraarterially with BBBD [24]. This toxicity can be substantially decreased with delayed high-dose sodium thiosulfate (STS), a thiol chemoprotectant [25,26]. Additional side effects which are known to occur secondary to the chemotherapy drugs, such as nausea, fatigue, and myelosuppression, occur in patients in the BBBD program. Of note, the above side effects and toxicities can often be avoided if standard BBBD patient care guidelines developed by the BBB Consortium are closely followed.

The above technique of BBBD has been performed at institutions participating in the BBB Consortium which includes the Ohio State University in Columbus, University of Oklahoma Health Science Center in Oklahoma City, University of Minnesota in Minneapolis, Cleveland Clinic Foundation in Cleveland, University of Kentucky in Lexington, Hadassah-Hebrew University Medical Center in Jerusalem, Centre Hospital Universitaire de Sherbrooke in Quebec, and Oregon Health and Science University, in Portland (the coordinating center). Standard guidelines for anesthesia, transfemoral arterial catheterization, radiographic assessment of disruption and of tumor response, mannitol, and chemotherapy infusion, and patient care guidelines, are used by participating BBBD centers. Since 1995, the BBB consortium has held an annual scientific meeting. The meetings have been partially funded by an NIH R13 grant, and provide a forum for the BBB Consortium to share advances, results, and problems with the current consortium clinical protocols, and to discuss future clinical trials. Following each meeting, a summary report is written by the meeting participants and submitted for publication [27–29].

CLINICAL BBBD RESULTS Since the goal of BBBD is enhanced delivery to the CNS, while preserving the patient’s neurocognitive functioning and quality of life, BBBD clinical protocols include an extensive neuropsychological test battery and quality-oflife questionnaire, which are completed at study entry and at follow-up. Excellent results have been obtained in patients with PCNSL, a highly chemosensitive tumor, using BBBD-enhanced delivery of methotrexate-based chemotherapy. It is well known that the prognosis for patients with PCNSL has improved dramatically with combined chemotherapy and radiation treatment. However, the risk of neurotoxicity associated particularly with whole-brain radiation therapy (WBRT) is substantial, especially in older patients [30]. Enhanced delivery approaches such as BBBD offer the possibility of eliminating WBRT and thus the associated neurotoxicity. A series of 74 PCNSL patients, with no prior radiotherapy, treated with methotrexate-based chemotherapy with osmotic BBBD, were reported by our clinical team [18]. The estimated 5-year survival of this series was 42% with 86% of patients in complete response at 1 year demonstrating no cognitive loss. Kraemer et al. have assessed the association of total dose intensity and survival in the 74 PCNSL patients [31]. The number of BBB disruptions and the cumulative quality of disruption scores demonstrated longer survival with increased dose intensity. The relationship between MRI changes and cognitive function was studied in a subset (n ¼ 16) of PCNSL patients treated with BBBD who were in complete response after a

Blood-Brain Barrier Disruption Chemotherapy Chapter

year of treatment. By the end of treatment, all patients’ cognitive function had improved, and T2 signal abnormalities associated with the enhancing tumor were stable, decreased, or resolved in 15 of 16 patients [32]. In patients with ocular involvement of PCNSL, intravitreal methotrexate has shown efficacy in inducing clinical remission with acceptable morbidity [33]. Our multicenter consortium results were reported in Angelov et al. [34]. In that series, the results of the protocol utilizing BBBD in conjunction with intraarterial methotrexate-based chemotherapy without WBRT were evaluated in 149 patients with newly diagnosed PCNSL. This group achieved a complete response rate of 56% and a partial response rate of 24%, for an overall response rate of 82%. The median overall survival (OS) was 3.1 years, with a 25% estimated survival at 8.5 years. The median progression-free survival (PFS) was 1.8 years. The 5-year and 7-year PFS were 31% and 25%. We were able to identify the risk-stratified groups based on age and KPS. For patients within the low-risk group (age < 60 and KPS  70) the median OS was 14 years, and a survival plateau was noted at 8 years [34]. Long-term cognitive results following BBBD chemotherapy without WBRT in patients with PCNSL were evaluated by Doolittle et al. [35]. Patients evaluated were in CR, in order to assess the impact of neurotoxicity without the confounding presence of infiltrative and often multifocal CNS disease. Neurocognitive examinations were given at a minimum of 2 years and for a maximum of 26 years, following treatment. The median interval from diagnosis to long-term evaluation was 12 years. Their results found that patients demonstrated a significant improvement in tests of attention/executive function from pretreatment to longterm evaluation. They also demonstrated improvement in tests of verbal memory [35]. Long-term cognitive outcomes have been compared among other forms of treatment for PCNSL. Eighty patients from four different PCNSL treatment regimens were evaluated with neurocognitive testing at a median interval of 5.5 years after treatment, and were compared with the baseline. Patients treated with the addition of WBRT to their methotrexate chemotherapy had significantly lower scores in attention/executive function, motor skills, and neuropsychological composite scores compared with the pretreatment baseline. T2 abnormalities on MRI were more frequent in patients treated with WBRT and were associated with worse neuropsychological and quality-of-life outcomes [36]. Recent advances in targeted immunotherapy have been made using novel therapeutic agents. However for the most part, these are still limited by the BBB. It has been reported that rituximab (Rituxan), an mAb which reacts specifically with the B-cell antigen CD20, induces apoptosis and may synergize with platinum drugs [37]. On the basis of these findings we have begun using rituximab intravenously the

10

149

evening before BBBD with carboplatin-based chemotherapy, thus delivering an mAb across the BBB. The CD20 + antibody rituximab has been included as an adjunct to current therapies in both newly diagnosed and in recurrent PCNSL. When added to the regimen, rituximab is infused 12 h before day 1 of monthly BBBD. Analysis of the clinical results following its use suggests a benefit. In a series of 24 patients treated with rituximab in combination with methotrexate-based chemotherapy and BBBD, an improved complete response rate of 75% was noted compared with a complete response rate of 56% in the previous series. The median PFS was 2.1 years and the median OS was 5.1 years, suggesting there is a survival benefit with the addition of rituximab to the methotrexate-based regimen [38]. Tyson et al. have reported sensitivity to carboplatinbased chemotherapy with BBBD in relapsed PCNSL [20]. Recurrent PCNSL remains a difficult treatment group; however, these patients have responded favorably to repeat BBBD with a carboplatin regimen in addition of rituximab. The results have been encouraging and the safety reasonable. We reported three patients who underwent a total of 152 monthly BBBD. There were no increased adverse events noted in the repeat procedures. This presents further opportunity for patients to have repeat barrier disruption procedures in the future should additional advances in therapeutics develop [39]. Anaplastic oligodendroglioma with allelic loss of heterozygosity on chromosome 1p and/or 19q are chemosensitive tumors, which respond well to alkylating agents. BBBD with chemotherapy has been safely performed in patients with recurrent disease who have failed previous temozolomide therapy. Patients were treated with melphalan (intraarterial), carboplatin (intraarterial), and etoposide phosphate (intravenous) in conjunction with BBBD. Preliminary results in 13 patients have indicated a complete or partial tumor response in five, stable disease in five, and progression in three [40]. BBBD with methotrexate intraarterial-based and carboplatin intraarterial-based chemotherapy in conjunction with BBBD has been successful in the treatment of children and young adults with germ cell tumors. Jahnke et al. have reported a total of 54 patients who were treated including primitive neuroectodermal tumor (PNET) (n ¼ 29), medulloblastoma (n ¼ 12), and germ cell tumors (n ¼ 13). The median OS for all patients was 2.8 years (2.5 for PNET, 1.7 for medulloblastoma, and 5.4 for germ cell tumors). Long-term survival was seen in 16 of 54 patients from 4 to 18 years after treatment [41]. Although CNS metastases occur much more frequently than primary brain tumors, treatment options are limited and chemotherapy in the setting of CNS metastases has not been widely studied. There remain current limitations and challenges in our understanding of the pathogenesis and treatments of metastatic tumors of the CNS. Progress

150

SECTION

II Innovative Chemotherapy Delivery

is needed in areas of identification of tumor-specific metastatic signatures that confer a metastatic potential to the CNS, both from a therapeutic as well as a potential preventative viewpoint. Preclinical models of CNS metastatic disease are still needed that mimic more accurately the clinical conditions. Standardization of imaging techniques will be useful in determining the therapeutic responses [42]. Still the use of enhanced chemotherapy delivery with barrier disruption has been shown useful and effective in the treatment of metastatic tumors. For example, platinumbased systemic chemotherapy is widely used in the treatment of ovarian cancer. Five patients with CNS metastases from ovarian (n ¼ 4) and endometrial (n ¼ 1) cancer, who refused or failed to respond to conventional treatment were treated with carboplatin (intraarterial) with or without BBBD, etoposide or etoposide phosphate (intravenous or intraarterial) and cyclophosphamide (intravenous). The primary gynecologic cancer was in remission after systemic treatment, before the development of CNS metastases. If residual brain lesions were present after the intraarterial chemotherapy, then focal radiation was given (see Table 10.1). As a case example, one of the patients with ovarian cancer developed a single, deep, temporal-occipital metastatic CNS lesion (see Fig. 10.3A and B). The patient refused brain surgery and was treated with carboplatin (intraarterial), cyclophosphamide (intravenous), and etoposide phosphate (intravenous) with BBBD. MRI showed dramatic response to chemotherapy. Radiosurgery was then given to the enhancing lesion. Following radiosurgery, the patient was in remission for 41 months and maintained full functional status (KPS ¼ 90).

The OS from the date of diagnosis of the gynecologic cancer ranged from 25 to 65 months, with an average of 47 months (see Table 10.1). The mean survival from the date of diagnosis of CNS metastases was 26 months. These results are among the best reported survivals for CNS metastases of ovarian cancer. Three of the five patients had a KPS of 80 or more before starting treatment; these three had the longest survivals and sustained a KPS of 80 or more during intraarterial or BBBD treatment. These findings suggest that further investigation of the role of BBBD-enhanced chemotherapy in CNS metastases is warranted.

FUTURE BBBD DIRECTIONS The occurrence of CNS metastases of systemic cancers far exceeds the number of primary malignant brain tumors. Current therapies such as radiosurgery are effective for short-term palliation of CNS metastases; however, often they do not provide long-term disease control. In many cases, WBRT used to treat CNS metastases has been associated with neurotoxicity. BBBD enables global delivery of chemotherapy to all cerebral circulations, and thus may offer a new treatment strategy for CNS metastases, administered before or after radiosurgery or WBRT. Neuroimaging techniques have become increasingly important in assessing the biological and physiological aspects of brain tumors. The BBB is an important obstacle to the delivery of both therapeutic and diagnostic imaging agents in primary and metastatic brain tumors. The ability to image infiltrative disease and to better

TABLE 10.1 Location and Number of Brain Metastases, Additional Treatment for Brain Metastases Location (and Number) of Brain Metastases

Additional Treatment for Brain Metastases

Survival (Months) From Diagnosis of Gynecologic Cancer

Survival (Months) From Diagnosis of Brain Metastases

1

Multiple deep and superficial supratentorial (4)

P: whole brain radiation

46

32

2

Left temporal-occipital (1)

A: stereotactic radiation

65

41

3

Right cerebellar hemisphere (1)

A: whole brain radiation

36

10

4

Left frontal (1), left parietal (1), right temporal (1)

None

25

9

5

Left cerebellar hemisphere (1)

A: stereotactic radiation

63

41

Patient

P, prior to intraarterial chemotherapy; A, after intraarterial chemotherapy, and survival (months) for five patients with ovarian (n ¼ 4) or endometrial (n ¼ 1) cancer, from diagnosis of primary cancer and from diagnosis of brain metastases.

Blood-Brain Barrier Disruption Chemotherapy Chapter

10

151

FIG. 10.3 MRI with gadolinium shows large, deep temporal-occipital brain metastases in a patient with a history of ovarian carcinoma (A). The patient underwent five courses of carboplatin (intraarterial), cyclophosphamide (intravenous), and etoposide phosphate (intravenous) with BBBD. MRI with gadolinium shows a dramatic response after BBBD chemotherapy (B). Radiosurgery was then given to the small, residual, enhancing lesion (arrow).

(A)

(B)

assess the extent of disease and actual tumor volume is critical. Varallyay et al. have shown, using ultrasmall superparamagentic iron oxide particles (USPIOs), improvement in imaging tumor microvasculature and larger areas of tumor enhancement, in some cases [43]. Delayed imaging has shown that the USPIO is taken up into tumor macrophages and reactive astrocytes, and is visualized histochemically [44]. Owing to the virus-like size of the USPIO, penetration of viral vectors may be monitored, when using gene therapy. Research has shown that USPIOs such as ferumoxytol aid morphological assessment of brain tumor location and extent on T1-weighted MRI. They are useful in dynamic susceptibility weighted (DSC) MRI of tumor vasculature due to the finding that they cross the BBBD in a delayed manner. They are therefore a blood pool agent initially, able to identify tumor vasculature more precisely than gadolinium-based agents, then cross into the brain interstitial space over 24–48 h where they become a delayed enhancing agent useful for intraoperative MRI. The USPIOs are taken up into inflammatory cells, particularly macrophages, over 24–48 h, becoming a potential marker for immune responsiveness and an adjunct to differentiate tumor progression from treatment effects, the so-called pseudoprogression [45,46].

SUMMARY BBB translational research evaluates toxicity and efficacy of global CNS delivery of chemotherapeutics in combination with chemoprotectants and/or mAbs. New clinical studies for chemotherapy-responsive primary and metastatic CNS tumors have been developed to deliver mAbs across the BBB. The studies are conducted by the participating BBB Consortium institutions.

ACKNOWLEDGMENTS The studies reported in this chapter were supported by a Veterans Administration Merit Review Grant; National Institutes of Health R01 Grants NS 44687, NS 34608, and NS 33618 from the National Institute of Neurological Disorders and Stroke (NINDS); R13 CA 86959 from the National Cancer Institute, NINDS, and the National Institute of Deafness and Other Communication Disorders; and PHS Grant 5 M01 RR000334.

REFERENCES [1] Groothuis DR, Vriesendorp FJ, Kupfer B, et al. Quantitative measurements of capillary transport in human brain tumors by computed tomography. Ann Neurol 1991;30:581–8. [2] Levin VA, Clancy TP, Ausman JI, Rall DP. Uptake and distribution of 3H-methotrexate by the murine ependymoblastoma. J Natl Cancer Inst 1972;48:875–83. [3] Groothuis DR. The blood-brain and blood-tumor barriers: a review of strategies for increasing drug delivery. Neuro-Oncology 2000;2:45–59. [4] Neuwelt EA. Mechanisms of disease: the blood-brain barrier. Neurosurgery 2004;54:131–42. [5] Doolittle ND, Muldoon LL, Culp AY, Neuwelt EA. Delivery of chemotherapeutics across the blood-brain barrier: challenges and advances. Adv Pharmacol 2014;71:203–43. https://doi.org/10.1016/ bs.apha.2014.06.002. Review. [6] Neuwelt EA, Barnett PA, Hellstrom KE, et al. Delivery of melanomaassociated specific immunoglobulin monoclonal antibody and Fab fragments to normal brain utilizing osmotic blood-brain barrier disruption. Cancer Res 1988;48:4725–9. [7] Neuwelt EA, Frenkel EP, Rapoport S, Barnett P. Effect of osmotic blood-bain barrier disruption on methotrexate pharmacokinetics in the dog. Neurosurgery 1980;7:36–43. [8] Neuwelt EA, editor. Implications of the blood-brain barrier and its manipulation. vol. 2. New York: Plenum Publishing Corporation; 1989. [9] Kroll RA, Neuwelt EA. Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means. Neurosurgery 1998;42:1083–100.

152

SECTION

II Innovative Chemotherapy Delivery

[10] Remson LG, McCormick CI, Sexton G, Pearse HD, Garcia R, Neuwelt EA. Decreased delivery and acute toxicity of cranial irradiation and chemotherapy given with osmotic blood-brain barrier disruption in a rodent model: the issue of sequence. Clin Cancer Res 1995;1:731–9. [11] Remsen LG, Marquez C, Garcia R, Thrun LA, Neuwelt EA. Efficacy after sequencing of brain radiotherapy and enhanced antibody targeted chemotherapy delivery in a rodent human lung cancer brain xenograft model. Int J Radiat Oncol Biol Phys 2001;51:1045–9. [12] Remsen LG, McCormick CI, Sexton G, et al. Long-term toxicity and neuropathology associated with the sequencing of cranial irradiation and enhanced chemotherapy delivery. Neurosurgery 1997;40:1034–42. [13] Dahlborg SA, Henner WD, Crossen JR, et al. Non-AIDS primary cns lymphoma: first example of a durable response in a primary brain tumor using enhanced chemotherapy delivery without cognitive loss and without radiotherapy. Cancer J Sci Am 1996;2:166–74. [14] Neuwelt EA, Pagel M, Barnett P, Glasberg M, Frenkel EP. Pharmacology and toxicity of intracarotid adriamycin administration following osmotic blood-brain barrier modification. Cancer Res 1981;41:4466–70. [15] Neuwelt EA, Barnett PA, Glasberg M, Frenkel EP. Pharmacology and neurotoxicity of cis-Diamminedichloroplatinum, bleomycin, 5-fluorouracil, and cyclophosphamide administration following osmotic blood-brain barrier modification. Cancer Res 1983;43:5278–85. [16] Fortin D, McCormick CI, Remsen LG, Nixon R, Neuwelt EA. Unexpected neurotoxicity of etoposide phosphate administered in combination with other chemotherapeutic agents after blood-brain barrier modification to enhance delivery, using propofol for general anesthesia, in a rat model. Neurosurgery 2000;47:199–207. [17] Dahlborg SA, Petrillo A, Crossen JR, et al. The potential for complete and durable response in nonglial primary brain tumors in children and young adults with enhanced chemotherapy delivery. Cancer J Sci Am 1998;4:110–24. [18] McAllister LD, Doolittle ND, Guastadisegni PE, et al. Cognitive outcomes and long-term follow-up results after enhanced chemotherapy delivery for primary central nervous system lymphoma. Neurosurgery 2000;46:51–61. [19] Doolittle ND, Miner ME, Hall WA, et al. Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors. Cancer 2000;88:637–47. [20] Tyson RM, Siegal T, Doolittle ND, Lacy C, Kraemer DF, Neuwelt EA. Current status and future of relapsed primary central nervous system lymphoma (PCNSL). Leuk Lymphoma 2003; 44:627–33. [21] Doolittle ND, Petrillo A, Bell S, Cummings P, Eriksen S. Blood-brain barrier disruption for the treatment of malignant brain tumors: the national program. J Neurosci Nurs 1998;30:81–90. [22] Roman-Goldstein S, Clunie DA, Stevens J, et al. Osmotic blood-brain barrier disruption: CT and radionuclide imaging. AJNR Am J Neuroradiol 1994;15:581–90. [23] Fortin D, McAllister LD, Nesbit G, et al. Unusual cervical spinal cord toxicity associated with intra-arterial carboplatin, intra-arterial or intravenous etoposide phosphate, and intravenous cyclophosphamide in conjunction with osmotic blood-brain barrier disruption in the vertebral artery. AJNR Am J Neuroradiol 1999;20:1794–802.

[24] Williams PC, Henner DW, Roman-Goldstein S, et al. Toxicity and efficacy of carboplatin and etoposide in conjunction with disruption of the blood-brain barrier in the treatment of intracranial neoplasms. Neurosurgery 1995;37:17–28. [25] Neuwelt EA, Brummett RE, Doolittle ND, et al. First evidence of otoprotection against carboplatin-induced hearing loss with a two-compartment system in patients with central nervous system malignancy using sodium thiosulfate. J Pharmacol Exp Ther 1998;286:77–84. [26] Doolittle ND, Muldoon LL, Brummett RE, et al. Delayed sodium thiosulfate as an otoprotectant against carboplatin-induced hearing loss in patients with malignant brain tumors. Clin Cancer Res 2001;7:493–500. [27] Doolittle ND, Anderson CP, Bleyer WA, et al. Importance of dose intensity in neuro-oncology clinical trials: summary report of the sixth annual meeting of the Blood-Brain Barrier Disruption Consortium. Neuro-Oncology 2001;3:46–54 [Posted to Neuro-Oncology, Doc. 00-039, November 3, 2000 ]. [28] Doolittle ND, Abrey LE, Ferrari N, et al. Targeted delivery in primary and metastatic brain tumors: summary report of the seventh annual meeting of the Blood-Brain Barrier Disruption Consortium. Clin Cancer Res 2002;8:1702–9. [29] Doolittle ND, Abrey LE, Bleyer WA, et al. New frontiers in translational research in neuro-oncology and the blood-brain barrier: Report of the tenth annual Blood-Brain Barrier Disruption Consortium meeting. Clin Cancer Res 2005;11(2 pt 1):421–8. [30] Abrey LE, DeAngelis LM, Yahalom J. Long-term survival in primary CNS lymphoma. J Clin Oncol 1998;16:859–63. [31] Kraemer DF, Fortin D, Doolittle ND, Neuwelt EA. Association of total dose intensity of chemotherapy in primary central nervous system lymphoma (human non-acquired immunodeficiency syndrome) and survival. Neurosurgery 2001;48:1033–41. [32] Neuwelt EA, Guastadisegni PE, Varallyay P, Doolittle ND. Imaging changes and cognitive outcome in primary CNS lymphoma after enhanced chemotherapy delivery. AJNR Am J Neuroradiol 2005;26(2):258–65. [33] Smith JR, Rosenbaum JT, Wilson DJ, et al. Role of intravitreal methotrexate in the management of primary central nervous system lymphoma with ocular involvement. Ophthalmology 2002;109:1709–16. [34] Angelov L, Doolittle ND, Kraemer DF, Siegal T, Barnett GH, Peereboom DM, et al. Blood-brain barrier disruption and intraarterial methotrexate-based therapy for newly diagnosed primary CNS lymphoma: a multi-institutional experience. J Clin Oncol 2009;27(21):3503–9. https://doi.org/10.1200/JCO.2008.19.3789. [35] Doolittle ND, Do´sa E, Fu R, Muldoon LL, Maron LM, Lubow MA, et al. Preservation of cognitive function in primary CNS lymphoma survivors a median of 12 years after enhanced chemotherapy delivery. J Clin Oncol 2013;31(31):4026–7. [36] Doolittle ND, Korfel A, Lubow MA, Schorb E, Schlegel U, Rogowski S, et al. Long-term cognitive function, neuroimaging, and quality of life in primary CNS lymphoma. Neurology 2013; 81(1):84–92. [37] Alas S, Ng CP, Bonavida B. Rituximab modifies the cisplatinmitochondrial signaling pathway, resulting in apoptosis in cisplatin-resistant non-Hodgkins lymphoma. Clin Cancer Res 2002;8:836–45. [38] Doolittle ND, Fu R, Muldoon LL, Tyson RM, Lacy C, Neuwelt EA. Rituximab in combination with methotrexate-based chemotherapy

Blood-Brain Barrier Disruption Chemotherapy Chapter

[39]

[40]

[41]

[42]

[43]

with blood–brain barrier disruption in newly diagnosed primary CNS lymphoma. Hematol Oncol 2013;31(S1):179. McGregor J, Bourekas E, Bell S. Repeat blood-brain barrier disruption in patients with recurrent primary central nervous system lymphoma. Neuro-Oncology 2008;10(5):759–915. ST-17. Guillaume DJ, Doolittle ND, Gahramanov S, Hedrick NA, Delashaw JB, Neuwelt EA. Intra-arterial chemotherapy with osmotic blood-brain barrier disruption for aggressive oligodendroglial tumors: results of a phase I study. Neurosurgery 2010;66(1):48–58. discussion 58. Jahnke K, Kraemer DF, Knight KR, Fortin D, Bell S, Doolittle ND, et al. Intraarterial chemotherapy and osmotic blood–brain barrier disruption for patients with embryonal and germ cell tumors of the central nervous system. Cancer 2008;112(3):581–8. Puhalla S, Elmquist W, Freyer D, Kleinberg L, Adkins C, Lockman P, et al. Unsanctifying the sanctuary: challenges and opportunities with brain metastases. Neuro-Oncology 2015;17(5):639–51. Varallyay P, Nesbit G, Muldoon LL, et al. Comparison of two super paramagnetic viral-sized iron oxide particles ferumoxides and

10

153

ferumoxtran-10 with a gadolinium chelate in imaging intracranial tumors. AJNR Am J Neuroradiol 2002;23:510–9. [44] Neuwelt EA, Varallyay P, Bago A, Muldoon LL, Nesbit G, Nixon R. Imaging of iron oxide nanoparticles by MR and light microscopy in patients with malignant brain tumours. Neuropathol Appl Neurobiol 2004;30(1):70. [45] Gahramanov S, Muldoon LL, Varallyay CG, Li X, Kraemer DF, Fu R, et al. Pseudoprogression of glioblastoma after chemo- and radiation therapy: diagnosis by using dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging with ferumoxytol versus gadoteridol and correlation with survival. Radiology 2013;266(3): 842–52. [46] Weinstein JS, Varallyay CG, Dosa E, Gahramanov S, Hamilton B, Rooney WD, et al. Superparamagnetic iron oxide nanoparticles: diagnostic magnetic resonance imaging and potential therapeutic applications in neurooncology and central nervous system inflammatory pathologies, a review. J Cereb Blood Flow Metab 2010;30(1):15–35.