Diagnostic impact of preoperative corticosteroids in primary central nervous system lymphoma.

PURPOSE: High dose corticosteroids are an effective tool for rapidly alleviating neurologic symptoms caused by intracranial mass lesions. However, there is concern that preoperative corticosteroids limit the ability to obtain a definitive pathologic diagnosis, particularly if imaging features suggest primary central nervous system lymphoma (PCNSL). METHODS: To explore the impact of preoperative corticosteroids in newly diagnosed PCNSL patients, from 2009 to 2018 treated at our institution. RESULTS: We identified 54 patients; 18 had received corticosteroids prior to biopsy or resection. Only in one case did the patient have a prior non-diagnostic biopsy, requiring a second procedure. The cumulative doses of preoperative dexamethasone ranged from 4 mg to 120 mg (mean 32 mg, median 24 mg), given over 1-14 days (mean 2 days, median 1 day), and the majority had received corticosteroids for only 1-2 days. There was a trend for a larger diameter of lesional T1 contrast enhancement for patients who received steroids (39 mm vs. 34 mm, p = 0.11). In this series of cases with pathologically and clinically proven PCNSL, preoperative corticosteroids had been given in a third of cases, suggesting that they may be given for symptomatic relief without compromising pathologic diagnosis. CONCLUSIONS: Despite the commonly held tenet that preoperative corticosteroids can obscure the pathologic diagnosis in PCNSL, this is likely not the case in the majority of patients who receive a short course preoperatively. Obtaining a second stereotactic scan to confirm continued presence of the lesion prior to tissue sampling may also mitigate these concerns.

Distinguishing Extravascular from Intravascular Ferumoxytol Pools within the Brain: Proof of Concept in Patients with Treated Glioblastoma.

BACKGROUND AND PURPOSE: Glioblastoma-associated macrophages are a major constituent of the immune response to therapy and are known to engulf the iron-based MR imaging contrast agent, ferumoxytol. Current ferumoxytol MR imaging techniques for localizing macrophages are confounded by contaminating intravascular signal. The aim of this study was to assess the utility of a newly developed MR imaging technique, segregation and extravascular localization of ferumoxytol imaging, for differentiating extravascular-from-intravascular ferumoxytol contrast signal at a delayed 24-hour imaging time point. MATERIALS AND METHODS: Twenty-three patients with suspected post-chemoradiotherapy glioblastoma progression underwent ferumoxytol-enhanced SWI. Segregation and extravascular localization of ferumoxytol imaging maps were generated as the voxelwise difference of the delayed (24 hours) from the early (immediately after administration) time point SWI maps. Continuous segregation and extravascular localization of ferumoxytol imaging map values were separated into positive and negative components. Image-guided biologic correlation was performed. RESULTS: Negative segregation and extravascular localization of ferumoxytol imaging values correlated with early and delayed time point SWI values, demonstrating that intravascular signal detected in the early time point persists into the delayed time point. Positive segregation and extravascular localization of ferumoxytol imaging values correlated only with delayed time point SWI values, suggesting successful detection of the newly developed extravascular signal. CONCLUSIONS: Segregation and extravascular localization of ferumoxytol MR imaging improves on current techniques by eliminating intrinsic tissue and intravascular ferumoxytol signal and may inform glioblastoma outcomes by serving as a more specific metric of macrophage content compared with uncorrected T1 and SWI techniques.

Osmotic blood-brain barrier disruption. Computerized tomographic monitoring of chemotherapeutic agent delivery.

The present study describes a canine model of transient reversible blood-brain barrier disruption with hyperosmolar mannitol infusion into the internal carotid artery. Studies in this model show that osmotic blood-brain barrier disruption before intracarotid infusion of methotrexate results in markedly elevated (therapeutic) levels of drug in the ipsilateral cerebral hemisphere. Levels in the cerebrospinal fluid correlate poorly and inconsistently with brain levels. Computerized tomograms in this canine model provide a noninvasive monitor of the degree, time-course, and localization of osmotic blood-brain barrier disruption.

Characterization of a new model of GM2-gangliosidosis (Sandhoff's disease) in Korat cats.

We have detected a disorder in Korat cats (initially imported from Thailand) that is analogous to human Sandhoff's disease. Pedigree analysis indicates that this disease in an autosomal recessive disorder in the American Korat. Postmortem studies on one affected cat showed hepatomegaly that was not reported in the only other known feline model of GM2-gangliosidosis type II. Histologic and ultra-structural evaluation revealed typical storage vacuoles. There was a marked deficiency in the activity of hexosaminidase (HEX) A and B in affected brain and liver as compared to controls. Electrophoresis of a liver extract revealed a deficiency of normal HEX A and B in the affected animals. The blocking primary enzyme immunoassay verified the presence of antigenically reactive HEX present in affected cat livers in quantities slightly elevated with respect to the normal HEX concentration in control cats. In leukocytes, obligate heterozygotes had intermediate levels of total HEX activity with a slight increase in the percent activity due to HEX A. Indeed, 4 of 11 phenotypically normal animals in addition to four obligate heterozygotes appear to be carriers using this assay. Affected brain and liver compared with control brain and liver contained a great excess of bound N-acetylneuraminic acid in the Folch upper-phase solids; thin-layer chromatography showed a marked increase in GM2-ganglioside. In summary, we have characterized the pedigree, pathology, and biochemistry of a new feline model of GM2-gangliosidosis which is similar to but different from the only other known feline model.

Primary intraocular lymphoma: an International Primary Central Nervous System Lymphoma Collaborative Group Report.

BACKGROUND: Primary intraocular lymphoma (PIOL) is an uncommon subset of primary central nervous system lymphoma. Because it is rare and difficult to diagnose, the natural history and optimal management are unknown. PATIENTS AND METHODS: A retrospective study of 83 HIV negative, immunocompetent PIOL patients was assembled from 16 centers in seven countries. RESULTS: Median age at diagnosis was 65. Median ECOG performance status was 0. Presenting symptoms included blurred vision, decreased visual acuity, and floaters. Median time to diagnosis was 6 months. Diagnosis was made by vitrectomy (74), choroidal/retinal biopsy (6) and ophthalmic exam (3). Eleven percent had positive CSF cytology. Initial treatment was categorized as focal in 23 (intra-ocular methotrexate, ocular radiotherapy) or extensive in 53 (systemic chemotherapy, whole brain radiotherapy). Six received none; details are unknown in one. Forty-seven relapsed: brain 47%, eyes 30%, brain and eyes 15%, and systemic 8%. Median time to relapse was 19 months. Focal therapy alone did not increase risk of brain relapse. Median progression free (PFS) and overall survival (OS) were 29.6 and 58 months, respectively, and unaffected by treatment type. CONCLUSION: Treatment type did not affect relapse pattern, median PFS or OS. Focal therapy may minimize treatment toxicity without compromising disease control.

What Does the Boxed Warning Tell Us? Safe Practice of Using Ferumoxytol as an MRI Contrast Agent.

BACKGROUND AND PURPOSE: Despite the label change and the FDA's boxed warning added to the Feraheme (ferumoxytol) label in March 2015, radiologists have shown increasing interest in using ferumoxytol as an MR imaging contrast agent as a supplement or alternative to gadolinium. The goals of this study were to provide information regarding ferumoxytol safety as an imaging agent in a single center and to assess how the Feraheme label change may affect this potential, currently off-label indication. MATERIALS AND METHODS: This retrospective study evaluated the overall frequency of ferumoxytol-related adverse events when used for CNS MR imaging. Patients with various CNS pathologies were enrolled in institutional review board-approved imaging studies. Ferumoxytol was administered as multiple rapid bolus injections. The risk of adverse events was correlated with demographic data/medical history. RESULTS: The safety of 671 ferumoxytol-enhanced MR studies in 331 patients was analyzed. No anaphylactic, life-threatening, or fatal (grade 4 or 5) adverse events were recorded. The overall proportion of ferumoxytol-related grade 1-3 adverse events was 10.6% (8.6% occurring within 48 hours), including hypertension (2.38%), nausea (1.64%), diarrhea (1.04%), and headache (1.04%). History of 1 or 2 allergies was associated with an increased risk of adverse events (14.61% versus 7.51% [no history]; P = .007). CONCLUSIONS: The frequency of mild ferumoxytol-related adverse events was comparable with literature results, and no serious adverse event was recorded. Although the recommendations in the boxed warning should be followed, serious adverse events appear to be rare, and with proper precautions, ferumoxytol may be a valuable MR imaging agent.

Enhancing the cytotoxicity of chemoradiation with radiation-guided delivery of anti-MGMT morpholino oligonucleotides in non-methylated solid tumors.

The DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) is epigenetically silenced in some tumors by MGMT gene promoter methylation. MGMT-hypermethylated solid tumors have enhanced susceptibility to the cytotoxic effects of alkylating chemotherapy such as temozolomide, compared with non-methylated tumors. In glioblastoma, subjects with MGMT hypermethylation have significantly longer survival rates after chemoradiotherapy. We report the first successful use of a non-ablative dose of ionizing radiation to prime human cancer cells to enhance the uptake of unmodified anti-MGMT morpholino oligonucleotide (AMON) sequences. We demonstrate >40% reduction in the in vitro proliferation index and cell viability in radiation-primed MGMT-expressing human solid tumor cells treated with a single dose of AMONs and temozolomide. We further demonstrate the feasibility of using a non-ablative dose of radiation in vivo to guide and enhance the delivery of intravenously administered AMONs to achieve 50% MGMT knockdown only at radiation-primed tumor sites in a subcutaneous tumor model. Local upregulation of physiological endocytosis after radiation may have a role in radiation-guided uptake of AMONs. This approach holds direct translational significance in glioblastoma and brain metastases where radiation is part of the standard of care; our approach to silence MGMT could overcome the significant problem of MGMT-mediated chemoresistance.

Imaging and nanomedicine for diagnosis and therapy in the central nervous system: report of the eleventh annual Blood-Brain Barrier Disruption Consortium meeting.

The blood-brain barrier (BBB) presents a major obstacle to the treatment of malignant brain tumors and other central nervous system (CNS) diseases. The Eleventh Annual Blood-Brain Barrier Disruption Consortium Meeting was convened to discuss recent advances and future directions in imaging and nanomedicine. Two sessions, one on Cell and Molecular Imaging in the CNS and another on Nanotechnology, Nanobiology, and Nanomedicine, were held March 17-18, 2005, in Portland, Ore. CNS imaging presentations targeted differentiating tumor, neural lesions, and necrosis from healthy brain tissue; methods of delivery of imaging agents across the BBB; and new iron oxide-based nanoparticle contrast agents for MR imaging. Nanobiology presentations covered the development of new nanotechnology and its use in imaging, diagnosis, and therapy in the CNS. Discussions at this meeting stressed the role of biotechnology in the convergence of CNS imaging and nanomedicine and are summarized in this article.

Pharmacology and neurotoxicity of cis-diamminedichloroplatinum, bleomycin, 5-fluorouracil, and cyclophosphamide administration following osmotic blood-brain barrier modification.

cis-Platinum, bleomycin, 5-fluorouracil, and cyclophosphamide were administered to rodent and canine models of osmotic blood-brain barrier modification to evaluate the relationship between tissue drug concentration in brain and the physiological and neuropathological effects of the drug. The toxicity studies were carried out in the canine, and the pharmacological studies were carried out in the rodent. Even without the osmotic procedure, intracarotid cis-platinum, in contrast to the other drugs, produced modification of the blood-brain barrier with resultant severe neurotoxicity. Osmotic blood-brain barrier modification was used to increase delivery of bleomycin and 5-fluorouracil to the ipsilateral brain region, but the increased delivery was associated with evident neurotoxicity. Cyclophosphamide administration in association with osmotic blood-brain barrier opening did not cause significant neural toxicity. These studies indicate that some chemotherapeutic agents given in association with osmotic blood-brain barrier opening can result in neurotoxicity. The corollary of the known limited neurotoxicity when these chemotherapeutic agents are used in a conventional manner appears to be due to the presence of the blood-brain barrier.

Pharmacology and toxicity of intracarotid adriamycin administration following osmotic blood-brain barrier modification.

The effect of reversible blood-brain barrier modification on the delivery of Adriamycin to the brain was studied in a rodent and canine model. Pharmacokinetic and physiological studies were done in these animals after a wide range of doses of Adriamycin (0.1 to 1.0 mg/kg) were administered into the carotid artery following osmotic barrier modification with mannitol. In the absence of barrier modification, no immunoreactive Adriamycin was detected in the cerebrum; whereas, following barrier modification, up to 4.5 micrograms of drug and/or metabolites per g of brain were found. Optimum tissue levels of Adriamycin and metabolites were achieved following barrier modification when the drug was administered by either bolus or slow continuous (15-min) infusion. Immunoreactive drug was identified in brain for up to 6 hr after administration. Significant functional neurotoxicity occurred at all dose levels, even at 0.1 mg/kg, a level at which Adriamycin concentration in the brain was below the level of detectability. Neuropathological examination revealed the presence of necrosis and hemorrhagic infarcts. Thus, these pharmacological and toxicity studies suggest that Adriamycin (or its metabolites) may produce significant clinical neurotoxicity when even small amounts penetrate the blood-brain barrier.

Possible sites of origin of human plasma ribonucleases as evidenced by isolation and partial characterization of ribonucleases from several human tissues.

The ribonucleases (RNases) present in a number of human tissues, including heart, brain, lung, and kidney, were purified, partially characterized, and compared in their properties to the previously described RNases from human liver, spleen, pancreas, and serum. The enzymes appeared to fall into two major classes: liver-spleen type RNase and plasma-type RNase. These two types of enzymes were present in varying proportions in all tissues examined. The extent to which the tissues studied possibly contribute to serum RNase levels is discussed.

Therapeutic efficacy of aortic administration of N-acetylcysteine as a chemoprotectant against bone marrow toxicity after intracarotid administration of alkylators, with or without glutathione depletion in a rat model.

Modulation of thiol levels may alter both the efficacy and toxicity of chemotherapeutic agents. We investigated cytoenhancement, using L-buthionine-[S,R]-sulfoximine (BSO) to reduce cellular glutathione levels prior to intracarotid alkylator administration. We also evaluated chemoprotection against chemotherapy-induced systemic toxicity when the thiol agents N-acetylcysteine (NAC) and sodium thiosulfate were administered into the descending aorta to limit brain delivery. BSO treatment reduced rat brain and intracerebral tumor glutathione levels by 50-65%, equivalent to the reduction in liver and s.c. tumor. BSO treatment significantly enhanced the toxicity of chemotherapy with carboplatin, melphalan, and etoposide phosphate against granulocytes, total white cells, and platelets. Intracarotid administration of NAC resulted in high delivery to the brain, whereas infusion via the descending aorta minimized brain delivery. When NAC, with or without sodium thiosulfate, was administered via aortic infusion prior to chemotherapy, the magnitude of the bone marrow toxicity nadir was minimized, even with BSO-enhanced myelosuppression. Thus, BSO depleted brain and brain tumor glutathione but thereby increased chemotherapy-induced myelosuppression. Surprisingly, although NAC was found to readily cross the blood-brain barrier when given into the carotid artery, aortic infusion of NAC resulted in minimal exposure to the central nervous system (CNS) vasculature because of rapid clearance. As a result, aortic infusion of NAC to perfuse bone marrow and minimize myelosuppression and toxicity to visceral organs could be performed without interfering with the CNS cytotoxicity of intracarotid alkylators, even after BSO depletion of CNS glutathione.

[3H]Methotrexate loss from the rat brain following enhanced uptake by osmotic opening of the blood-brain barrier.

Right brain regions of anesthetized rats were loaded with [3,5,7-3H]methotrexate ([3H]MTX) or with [14C]sucrose by infusing the tracers into the right carotid artery, after the blood-brain barrier had been opened by right carotid infusion of a hypertonic arabinose solution. During the 6 hr following the procedure, the [3H]MTX concentration in 7 right-sided brain regions, when normalized to the plasma concentration integral during tracer infusion, fell, with an average half-time of 4.8 hr as compared to less than 20 min for the initial rate of loss [14C]sucrose. Right-left brain concentration differences 3 hr after treatment were statistically significant (p less than 0.05) for [3H]MTX but not for [14C]sucrose. The results indicate that intracerebral [3H]MTX is lost more slowly than is intracerebral [14C]sucrose, possibly because [3H]MTX enters brain cells, whereas [14C]sucrose remains largely extracellular.

Delivery of melanoma-associated immunoglobulin monoclonal antibody and Fab fragments to normal brain utilizing osmotic blood-brain barrier disruption.

Iodinated monoclonal antibodies (IgG 96.5 and two monomeric Fab fragments 96.5 and 48.7) to melanoma-associated antigens were administered after osmotic blood-brain barrier (BBB) opening in normal rats. Osmotic BBB disruption significantly (P less than 0.0001) increased monoclonal antibody delivery to the brain. Following BBB opening and intracarotid administration, there was no difference in the disrupted brain concentration integral area under the curve between Fab and IgG over the 72-h experimental period. However, Fab concentration in the disrupted brain was initially higher than IgG, and the clearance was more rapid (P less than 0.0001), decreasing 50% by approximately 4.5 h compared to 25.5 h for IgG. Plasma clearance was also more rapid for the Fab than IgG. The levels decreased 50% by 1.5 h for Fab and 15 h for IgG. The route and timing of antibody infusion had a significant effect on delivery to the disrupted brain with the Fab fragments but not with the intact IgG. Antibody recovered from disrupted brain retained its immunological reactivity as measured by a cell binding assay for at least 24 h. IgG and Fab delivery to the ipsilateral brain after BBB disruption increased (P less than 0.001) with increasing dose over a more than 3-log dose range. These data provide information applicable to the therapeutic use of monoclonal antibodies in brain tumor treatment.

Growth of human lung tumor in the brain of the nude rat as a model to evaluate antitumor agent delivery across the blood-brain barrier.

We have developed a brain tumor model in the nude rat utilizing NCI-N417D human small cell carcinoma of the lung grown both intracerebrally and s.c. The median latency period from the time of intracerebral tumor inoculation to the onset of neurological symptoms is 13 days with an intracerebral tumor take rate of 91% (29 of 32). The median survival is 13 days, and all animals were dead by Day 26. The tumor is discrete, well circumscribed, with occasional leptomeningeal spread and with minimal evidence of surrounding cerebral edema. Intracerebrally, this tumor is usually impermeable to Evan's blue:albumin (Mr 68,500) but not fluorescein (Mr 376). Although variable, the intracerebral tumor is less permeable to methotrexate than is the same tumor grown s.c. in the same animal (P less than 0.005). The intraarterial and i.v. routes of methotrexate administration in the presence and absence of blood-brain barrier opening were evaluated. Drug delivery to the intracerebral tumor and ipsilateral brain was significantly (P less than 0.025) greater when the methotrexate was given intraarterially and was significantly (P less than 0.0025) increased after osmotic blood-brain barrier opening. After barrier opening, methotrexate concentration was enhanced 3- to 4-fold in tumor and 10- to 20-fold in brain around tumor. Thus, the nude rat provides a model to investigate the biology and therapeutic responsiveness of human small cell carcinoma of the lung grown intracerebrally where it develops a blood-tumor barrier similar to that seen in humans. This model further provides the unique opportunity to investigate the role of osmotic blood-brain barrier opening in the treatment of a tumor which is sensitive to chemotherapeutic agents and for which tumor-specific monoclonal antibodies are available.

In vitro and animal studies of sodium thiosulfate as a potential chemoprotectant against carboplatin-induced ototoxicity.

When carboplatin (cis-diammine-1,1-cyclobutane-dicarboxylato-platinum) delivery to brain tumors is optimized with osmotic blood-brain barrier disruption (BBBD), high frequency hearing loss can result. Treatment with sodium thiosulfate (STS) blocked carboplatin cytotoxicity against the LX-1 human small cell lung carcinoma cell line in vitro. STS decreased carboplatin-induced ototoxicity in a guinea pig model, as determined by electrophysiological measurements and analysis of inner ear outer hair cell numbers. Protection was found when STS was administered up to 8 h subsequent to carboplatin but not 24 h after carboplatin. In a rat model of osmotic BBBD, STS was neurotoxic when given immediately after BBBD but not when given 60 min after BBBD, when the barrier is reestablished. Thus, delayed administration of STS may provide a mechanism to reduce the cochlear toxicity caused by BBBD-enhanced carboplatin delivery to the brain.

Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy.

PURPOSE: To examine behavioral dimensions of treatment outcomes for patients receiving cranial irradiation. Radiation encephalopathy is one of these and refers to significant cognitive and emotional dysfunction following radiation therapy to the brain. Issues of definition, estimated incidence, pathophysiologic mechanisms, and recommended research designs are reviewed in relationship to functional neurobehavioral outcomes. PATIENTS AND METHODS: Twenty-nine studies of adults receiving therapeutic cranial irradiation (TCI) involving 748 patients and 18 studies of prophylactic cranial irradiation (PCI) involving 368 patients are reviewed. Assessment of patient outcomes are summarized for research published since 1980, with specific attention to adverse changes in cognitive and emotional functioning. RESULTS: Analyses revealed that 213 TCI patients and 100 PCI patients showed encephalopathy attributed to radiation. Manifestations of the late delayed effects of radiotherapy on brain function are related to patient age, total dose of irradiation, fraction sizes, and timing of chemotherapy. Radiation encephalopathy appears to be more common than the pathologic tissue injury of radiation necrosis. Accurate diagnosis of these neurobehavioral sequelae can require follow-up over a period of years with sensitive assessment procedures. CONCLUSIONS: It is likely that the true incidence of treatment-related side effects of cranial irradiation in adults who survive more than 6 months without brain tumor growth or recurrence has been significantly underestimated. Research designs that include formal neuropsychologic assessment in conjunction with other neurodiagnostic tests can provide more comprehensive evaluation of long-term neurobehavioral outcomes.

Primary CNS lymphoma treated with osmotic blood-brain barrier disruption: prolonged survival and preservation of cognitive function.

Combination chemotherapy with or without radiotherapy has had only modest efficacy in the treatment of primary CNS lymphoma. Median survival of these patients, treated primarily with radiotherapy, is 13 months; 5-year survival is less than 5%. Thirty consecutive non-acquired immune deficiency syndrome patients with primary CNS lymphoma were treated with barrier-dependent chemotherapy using intraarterial mannitol to open the blood-brain barrier (BBB). Follow-up included extensive neuropsychologic testing of all patients. Thirteen patients received cranial radiation 1 to 9 months before referral (group 1). Seventeen patients received initial BBB disruption chemotherapy with subsequent radiation only for tumor progression or recurrence (group 2). The difference in median survivals from diagnosis--17.8 months for group 1 and 44.5 months for group 2--was statistically significant (P = .039). Group 1 survival is comparable with the 20-month median survival of a historical series of patients (n = 208) treated with radiotherapy with or without chemotherapy. Group 2 patient survival represents an advance in the survival of CNS lymphoma and was associated with preservation of cognitive function in six of seven nonirradiated complete responders observed for 1 to 7 years. Patient toxicity was manageable in this intensive therapeutic regimen. In this series, a plateau in survival curves suggests that a major portion of these patients may be cured without the neuropsychologic sequelae associated with cranial radiation.

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.

The sequence of chemotherapy administered prior to cranial irradiation rather than the more traditional order of radiation followed by chemotherapy is currently being evaluated. This rodent study was designed to assess the sequencing of radiation therapy and chemotherapy administered with osmotic blood-brain barrier disruption (BBBD). Drug delivery and acute toxicity were evaluated. Two clinically relevant chemotherapy regimens were given with BBBD: intraarterial methotrexate (MTX, 1 g/m2), or a combination of intraarterial carboplatin (200 mg/m2) and i.v. etoposide (200 mg/m2). In a randomized protocol, the standard rodent model of 2000 cGy as a single fraction using parallel opposed portals was administered 30 days prior to, concurrent with (24 h prior), or 30 days after these two chemotherapeutic regimens. A total of 72 animals was evaluated in this study. The administration of external beam radiation therapy either prior to or concurrent with the administration of a high molecular weight marker 14C-labeled dextran 70 (Mr 70,000), or a low molecular weight marker 3H-labeled MTX (Mr 456) resulted in a statistically significant (P < 0.01) decrease in drug delivery when compared to animals not receiving cranial irradiation. Seizures were observed in 26% of the animals that received radiation prior to the administration of intraarterial MTX after BBBD. It did not matter whether the radiotherapy was administered 30 days prior to or concurrent with MTX. Seizures were not seen in any other group. The mortality in animals receiving radiotherapy 30 days prior to chemotherapy was significantly (P = 0.03) higher than the mortality in control animals receiving chemotherapy after osmotic BBBD, but no radiation. Drug delivery was significantly decreased when the animals received prior radiotherapy; the administration of radiation prior to MTX with BBBD resulted in an increased incidence of seizures, and there was a significant increase in mortality when cranial irradiation was given 30 days prior to chemotherapy administered with BBBD. With regard to delivery and toxicity, chemotherapy with BBBD administered prior to radiotherapy may have advantages over the other sequences utilizing chemotherapy and cranial irradiation.

Delayed administration of sodium thiosulfate in animal models reduces platinum ototoxicity without reduction of antitumor activity.

Platinum-based chemotherapeutic agents, such as carboplatin and cisplatin, are effective against many human tumors, but their use may be limited by a high incidence of ototoxicity. Delayed administration of the chemoprotective agent sodium thiosulfate (STS) reduces the ototoxicity of carboplatin in a guinea-pig model, when given up to 8 h after the chemotherapy, and also reduces hearing loss in patients given carboplatin with osmotic blood-brain barrier opening for treatment of brain tumors. We tested whether STS, given at times that achieved otoprotection, could impact the chemotherapeutic efficacy of carboplatin. The impact of STS was evaluated by measuring the onset of growth of LX-1 human small cell lung carcinoma s.c. xenografts in the nude rat. When STS was administered as two boluses, 2 and 6 h after treatment with carboplatin and etoposide, there was a decrease in the time to tumor progression. In contrast, when STS administration was delayed until 8 h after carboplatin/etoposide, there was no reduction in the antitumor cytotoxicity of the chemotherapy. STS infusion did not significantly affect ultrafilterable platinum pharmacokinetics in the guinea pig. To explore the potential wider applicability of STS, in a pilot study we tested its efficacy against cisplatin ototoxicity. Delayed administration of STS, 2 h after cisplatin, was protective against cisplatin-induced ototoxicity in the guinea pig model, as determined by electrophysiological measures. On the basis of these data, we suggest that delayed administration of STS may provide a mechanism to reduce the ototoxicity caused by administration of carboplatin or cisplatin for both central nervous system and systemic cancer chemotherapy.