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Salvage Radioimmunotherapy With Murine Iodine-131–Labeled Antitenascin Monoclonal Antibody 81C6 for Patients With Recurrent Primary and Metastatic Malignant Brain Tumors: Phase II Study Results

From the Departments of Surgery, Medicine, Pathology, Radiology, and Cancer Center Biostatistics, Duke University Medical Center, Durham, NC.

Address reprint requests to David A. Reardon, MD, Department of Surgery, Division of Neurosurgery, Duke University Medical Center, Box 3624, Durham, NC, 27710; e-mail: reard003{at}mc.duke.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: To assess the efficacy and toxicity of intraresection cavity iodine-131–labeled murine antitenascin monoclonal antibody 81C6 (¹³¹I-m81C6) among recurrent malignant brain tumor patients.

PATIENTS AND METHODS: In this phase II trial, 100 mCi of ¹³¹I-m81C6 was injected directly into the surgically created resection cavity (SCRC) of 43 patients with recurrent malignant glioma (glioblastoma multiforme [GBM], n = 33; anaplastic astrocytoma [AA], n = 6; anaplastic oligodendroglioma [AO], n = 2; gliosarcoma [GS], n = 1; and metastatic adenocarcinoma, n = 1) followed by chemotherapy.

RESULTS: With a median follow-up of 172 weeks, 63% and 59% of patients with GBM/GS and AA/AO tumors were alive at 1 year. Median overall survival for patients with GBM/GS and AA/AO tumors was 64 and 99 weeks, respectively. Ten patients (23%) developed acute hematologic toxicity. Five patients (12%) developed acute reversible neurotoxicity. One patient (2%) developed irreversible neurotoxicity. No patients required reoperation for radionecrosis.

CONCLUSION: In this single-institution phase II study, administration of 100 mCi of ¹³¹I-m81C6 to recurrent malignant glioma patients followed by chemotherapy is associated with a median survival that is greater than that of historical controls treated with surgery plus iodine-125 brachytherapy. Furthermore, toxicity was acceptable. Administration of a fixed millicurie dose resulted in a wide range of absorbed radiation doses to the SCRC. We are now conducting a phase II trial, approved by the US Food and Drug Administration, using patient-specific ¹³¹I-m81C6 dosing, to deliver 44 Gy to the SCRC followed by standardized chemotherapy. A phase III multicenter trial with patient-specific dosing is planned.

	INTRODUCTION

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Outcome for adults with primary malignant brain tumors remains unacceptable. Although temozolomide plus radiotherapy has recently been shown to improve outcome for newly diagnosed glioblastoma multiforme (GBM) patients,¹ tumor progression occurs within 1 to 2 years in most patients. After recurrence, outcome is dismal due to ineffective salvage therapies.² Most tumors recur at or adjacent to the site of origin indicating that failure to eradicate local tumor growth is a major factor contributing to poor outcome.³ For this reason, we have focused on augmenting local control to improve overall outcome by administering tumor-associated radiolabeled monoclonal antibodies (mAbs) directly into spontaneous tumor cysts, surgically created resection cavities (SCRCs), the intrathecal space, and solid tumors.^4-7

Tenascin, an extracellular matrix hexabrachion glycoprotein, is expressed ubiquitously in high-grade gliomas and in breast, lung, and squamous cell carcinomas, but not normal brain.^8,9 81C6, a murine immunoglobulin G2b mAb that binds an epitope within the alternatively spliced fibronectin type III region of tenascin,^9-11 specifically reacts with tenascin-expressing tumors¹² and can delay tumor growth and induce apparent cures in flank and intracranial xenograft models.^13-15 Prior phase I studies established the maximum-tolerated dose (MTD) of iodine-131–labeled murine 81C6 (¹³¹I-m81C6) mAb injected into the SCRC of patients with newly diagnosed and recurrent malignant brain tumors to be 120 and 100 mCi, respectively.^5,6 In a subsequent phase II study for newly diagnosed patients, administration of 120 mCi of ¹³¹I-m81C6 followed by conventional radiotherapy and chemotherapy achieved median survivals of 87 and 79 weeks among all patients (n = 33) and those with GBM (n = 27), respectively. Toxicity was limited to reversible hematologic events in 27% of patients and neurologic deficits in 15% of patients.⁷ We now report a phase II study using 100 mCi of ¹³¹I-m81C6 in adults with recurrent malignant brain tumors.

	PATIENTS AND METHODS

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Patient Eligibility and Treatment
Eligible patients had a confirmed histologic diagnosis of recurrent supratentorial primary malignant tumor and were candidates for resection. Patients with tumors that were infratentorial, diffusely infiltrating, multifocal, or that had intraventricular access or subependymal spread were ineligible. Histopathologic samples from initial surgery were centrally reviewed at Duke University Medical Center (DUMC), and underwent immunoreactivity testing for tenascin as previously described.⁷ Patients were required to be older than 3 years, have a Karnofsky performance status (KPS) of 60%, and satisfy additional, previously described, eligibility requirements.⁷

Patients underwent a gross total resection (GTR) and placement of a Rickham reservoir and catheter into the SCRC. Contrast-enhanced magnetic resonance imaging (MRI) was obtained within 48 hours of resection to confirm that residual tumor did not extend more than 1.0 cm beyond the SCRC margin. Rickham catheter patency and SCRC integrity were confirmed by injecting technetium-99m (^99mTc) –labeled albumin or diethylenetriamine pentaacetic acid into the Rickham reservoir and obtaining gamma camera images immediately, then 4 and 24 hours later. Patients with subgaleal or subarachnoid leakage were not eligible. A baseline [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG PET) scan was obtained postresection. Before and 30 to 120 days after treatment, patients were tested for circulating antibodies to m81C6 as previously described.¹⁶

Eligible patients received four drops of a saturated solution of potassium iodine and 75 µg of liothyronine sodium (Cytomel; SmithKline Beecham, Pittsburgh, PA) daily from 48 hours before to 16 days after ¹³¹I-m81C6. The Rickham reservoir was accessed with a 25-gauge needle using sterile technique and up to 6 mL of SCRC cyst fluid was removed when possible. A volume of 6 mL of 81C6 mAb (20 mg) labeled with 100 mCi of ¹³¹I was injected into the reservoir. The reservoir and catheter were then flushed with the previously aspirated, sterile SCRC fluid. Patients remained in radiation isolation until the whole-body retention of ¹³¹I was 30 mCi, as measured by a cross-calibrated radiation survey meter. Before discharge, a brain MRI was performed and radionuclide gamma imaging as well as serial blood samples were obtained to assess the biodistribution of ¹³¹I.

The DUMC Investigational Review Board approved this study. Investigational review board–approved informed consent was obtained from each patient.

Antibody Production and Labeling
The 81C6, grown in athymic mice ascites, was purified over a Sepharose-staphylococcal protein-A (Amersham Biosciences Corporation, Piscataway, NJ) column followed by polyethylenimine ion exchange chromatography. US Food and Drug Administration manufacturing and testing guidelines for mAb products were followed for each clinical batch.¹⁷ The 81C6 was radiolabeled using a modified Iodo-Gen procedure (Pierce Chemical Co, Rockford, IL). All preparations had 75% immunoreactivity, with 95% of the label eluting as immunoglobulin G on high-pressure liquid chromatography and precipitating with trichloroacetic acid.

Pharmacokinetics and Dosimetry
Absorbed dose calculations for the SCRC, whole body, and bone marrow were performed using a serial, two-compartment system to model ¹³¹I-m81C6 pharmacokinetics, where the SCRC and the whole body (not including the SCRC) were assumed to be the first and second compartments, respectively.¹⁸ Postoperative MRI images (2-mm-thick slices, noninterleaved, 0-mm spacing) were used to generate a three-dimensional reconstruction of the head and SCRC (VoxelView 2.5.4; Vital Images, St Paul, MN). The calculated SCRC volume was used to estimate the initial SCRC activity, where a uniform activity concentration was assumed. Depth-dose calculations of the SCRC interface, 2-cm-thick margin, and normal brain were then performed.¹⁸

Toxicity and Response Determinations
After ¹³¹I-m81C6, patients were monitored continually with initial follow-up within 1 month of treatment and CBCs were monitored weekly for 8 weeks. Adjuvant chemotherapy was prescribed for 1 year beginning approximately 4 weeks after ¹³¹I-m81C6. Because of variability in chemotherapy regimens administered before study enrollment, chemotherapy after ¹³¹I-m81C6 was prescribed on an individualized, best clinical management basis using standard dosing schedules of conventional salvage chemotherapeutics such as temozolomide, lomustine, irinotecan, and etoposide. Patients were re-evaluated before chemotherapy was initiated and every 8 to 12 weeks during chemotherapy. Evaluations continued every 3 months for year 1, every 4 months for year 2, and biannually thereafter. At each evaluation, a complete physical examination, KPS rating, CBC, biochemical profile, and contrast MRI were performed. FDG PET scans were obtained as clinically indicated. Thyroid function was assessed within 1 to 2 months of ¹³¹I-m81C6 and every 6 to 12 months thereafter. Human antimouse antibody (HAMA) titers were measured within 6 months of ¹³¹I-m81C6.

National Cancer Institute Common Toxicity Criteria, version 2.0 (Bethesda, MD), were used to score toxicity. Although seizures were recorded, they were not considered an indication of neurotoxicity because of their expected frequency in this disease setting. The precise etiology of neurotoxicity following ¹³¹I-m81C6 was difficult to define because neither clinical features nor radiographic findings reliably distinguished recurrent tumor from treatment-induced necrosis. Although stereotactic biopsy is limited by volume sampling, it remains the definitive diagnostic tool of focal brain lesions. Therefore, the etiology of observed neurotoxicity was based on stereotactic biopsy whenever possible.

Progressive disease was defined by more than 25% increase in the enhancing tumor cross-sectional area or radiographically new lesions that were also hypermetabolic on FDG PET scan; clinical deterioration and a more than 25% increase in enhancing tumor or radiographically new lesions; or biopsy-proven recurrent tumor.

Statistical Analysis
In this single-stage phase II study of recurrent malignant brain tumor patients, 1-year survival after ¹³¹I-m81C6 was the primary end point. Our design provided 90% power at the .1 significance level to detect a 1-year survival of 40% to 60%, based on outcome achieved among recurrent GBM patients treated with iodine-125 (¹²⁵I) brachytherapy.¹⁹

The method of Kaplan and Meier²⁰ was used to estimate survival distributions measured from ¹³¹I-m81C6 administration to death or last contact. Subgroup differences in survival were assessed with log-rank tests.²¹ The Cox proportional hazards model²² was also used to investigate various prognostic factors, including age (< 50 v 50 years), KPS (< 90 v 90), SCRC volume (< 14 v 14 cm³), and SCRC dose (< 40 v 40 to 48 v > 48 Gy). Logistic regression was used to examine the effect of cavity size as well as ¹³¹I-m81C6 absorbed doses to the 2-cm SCRC interface on toxicity.

	RESULTS

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Patient Characteristics
The study population included 43 patients treated at DUMC between October 1996 and October 2003 (Table 1). Approximately 5% of screened patients were excluded because of subgaleal leakage on the postoperative flow study. This problem appeared to relate to SCRC proximity to the ventricular system rather than SCRC size.

HAMA
HAMA immunoassays, obtained on 34 patients within 2 to 26.1 weeks of treatment, were positive in 27 of 34 patients (79%; Table 2). No observed toxicity was related to HAMA reactivity.

Additional significant toxicities included thrombosis (grade 3, n = 5 [12%]; grade 4, n = 4 [9%]), wound infection (grade 3, n = 5 [12%]), and hypothyroidism (grade 2, n = 2 [5%]).

Biopsies and Reoperation
Nineteen (44%) patients underwent surgical procedures after ¹³¹I-m81C6, including 15 stereotactic biopsies and four craniotomies. Six biopsies (40%) showed gliosis and necrosis, and nine biopsies (60%) demonstrated recurrent tumor. Recurrent tumor was documented in the four patients who underwent repeat craniotomy.

Response/Survival Data
With a median follow-up of 172 weeks, five patients (12%) are alive, including three (37.5%) with anaplastic astrocytoma/anaplastic oligodendroglioma (AA/AO) (median follow-up, 161 weeks) and two (6%) with GBM/gliosarcoma (GS; 100.3- and 123-week follow-up, respectively). Median overall survival (OS) for all patients, those with GBM/GS, and those with AA/AO, was 68.6 weeks (95% CI, 38.8 to 98.0 weeks), 63.9 weeks (95% CI, 38.8 to 90.0 weeks), and 98.6 weeks (95% CI, 27.8 to infinity), respectively (P for GBM/GS v AA/AO = .11; Fig 1). One-year survival probability for all patients, those with GBM/GS and those with AA/AO was 60% (95% CI, 46 to 76), 59% (95% CI, 44 to 78), and 63% (95% CI, 37 to 100), respectively.

View larger version (9K): [in this window] [in a new window]   Fig 1. Kaplan-Meier overall survival estimates for all patients after stratification by histology. GBM, glioblastoma multiforme; GS, gliosarcoma.

	DISCUSSION

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The primary objective of the current phase II study was to assess the impact on survival of 100 mCi of ¹³¹I-m81C6 administered into the SCRC of recurrent malignant brain tumor patients. A secondary objective was to assess further the feasibility and toxicity of this approach among such patients. Patients were previously treated with XRT (93%) and/or chemotherapy (51%). After ¹³¹I-m81C6, most patients received systemic chemotherapy (58%); however, 35% received no additional therapy. Median OS was 64 and 99 weeks for recurrent GBM/GS (n = 34) and AA/AO (n = 8) patients, respectively, and 60% of all patients were alive at 1 year.

We demonstrated previously that ¹³¹I-m81C6 administered into the SCRC of newly diagnosed malignant glioma patients is well tolerated in a phase I study that established the ¹³¹I-m81C6 MTD to be 120 mCi. Delayed neurologic toxicity was dose limiting, and the only significant non-neurologic toxicity was hematologic, consisting of grade 3 or grade 4 events in 12% and 2.5% of patients, respectively.⁶ Despite the dose-escalation design, the median OS for all patients and those with GBM was 79 and 69 weeks, respectively. In a follow-up phase II study in which newly diagnosed malignant glioma patients received 120 mCi of ¹³¹I-m81C6 followed by conventional XRT and systemic chemotherapy, the median OS was 89 and 79 weeks for all patients and those with GBM, respectively.⁷ Only two patients (2.7%) combined from our phase I and II trials required debulking resection for radionecrosis.

Similarly, we established the ¹³¹I-m81C6 MTD of among recurrent malignant brain tumor patients to be 100 mCi in a prior phase I study. Dose-limiting toxicity was neurologic. The median survival for all patients (n = 34) and those with recurrent GBM (n = 26) was 60 and 56 weeks, respectively.⁵

This study confirms that 100 mCi of ¹³¹I-m81C6 administered into the SCRC is well tolerated among recurrent malignant glioma patients. Acute, primarily reversible, hematologic toxicity was the most common significant adverse event (23% of patients). Acute neurologic toxicity developed in six patients (12%) and resolved spontaneously or after short-term corticosteroid administration in all but one patient. No patients required surgery to debulk radiation necrosis. In contrast, up to half of patients treated with alternative strategies to boost radiation therapy to the primary tumor bed, including stereotactic radiosurgery (SRS) and the implantation of ¹²⁵I-radiolabeled beads (¹²⁵I brachytherapy), may require secondary craniotomy to debulk radionecrosis.^23-33

The median OS achieved in this study compares favorably with that reported for other salvage systemic therapies. The median OS for patients with GBM treated with temozolomide at first relapse was approximately 32 weeks.³⁴ Similarly, the median OS achieved with eight consecutive investigational salvage therapies for recurrent malignant glioma patients was 47 weeks for patients with grade 3 anaplastic gliomas and only 25 weeks for those with GBM.² Furthermore, our results compare favorably with those achieved with alternative strategies to boost radiation delivered to the primary tumor site, including SRS and ¹²⁵I-brachytherapy.^19,23-33 Shrieve et al³⁰ reported median OS of 46 and 41 weeks for patients with recurrent GBM treated with ¹²⁵I-brachytherapy and SRS, respectively, whereas Larson reported a median OS of 52 weeks for recurrent GBM patients who received ¹²⁵I-brachytherapy after a GTR.¹⁹ The latter group most likely represents the closest comparative group to the GBM patients treated during the current study. Finally, the results of the current trial also compare favorably to the administration of interstitial chemotherapy using carmustine-loaded polymers (Gliadel; Guilford Pharmaceuticals Inc, Baltimore, MD). Among 110 treated patients, the median survival was 31 weeks.¹⁶

The encouraging results of this study must be interpreted cautiously because of several potential limitations. Specifically, this was a single-institutional effort involving a modest number of patients with overall favorable KPS who underwent GTR. This study was conducted with a fixed dose of ¹³¹I-m81C6 (100 mCi) as required by the US Food and Drug Administration. Perhaps the most important lesson learned from this approach is that fixed millicurie dosing leads to a wide range of absorbed radiation doses to the 2-cm SCRC margin. For example, the absorbed dose to the 2-cm SCRC margin in our prior phase II study in which newly diagnosed patients received a fixed, 120-mCi ¹³¹I-m81C6 dose, ranged between 2 and 119 Gy.⁷ Similarly, the administration of a fixed 100-mCi ¹³¹I-m81C6 dose in the current study resulted in a 2-cm SCRC margin dose between 18 and 186 Gy.

On the basis of analysis of the relationship between progressive tumor and radionecrosis, we have determined that 44 Gy (± 10%) is the optimal dose to the 2-cm SCRC margin. Specifically, patients who receive less than 44 Gy have a higher rate of tumor recurrence, whereas those who receive significantly more than 44 Gy have a higher rate of radionecrosis.¹⁸ The findings of the current study support this relationship, although they require validation in a larger trial designed to assess this hypothesis. Specifically, the low rate of neurotoxicity observed in this study most likely reflects that the majority of patients received less than 48 Gy. Furthermore, patients who received 40 to 48 Gy had a two-fold higher OS compared with those who received less than 40 Gy. The variables determining absorbed dose are SCRC volume, SCRC residence time, and administered dose. One can calculate SCRC residence time from a dosimetry study in which a small dose of ¹²³I- or ¹³¹I-labeled 81C6 is administered before a therapeutic ¹³¹I-m81C6 dose. By taking into account SCRC volume, measured on pretreatment MRI, one can then calculate a patient-specific ¹³¹I-m81C6 therapeutic dose, to achieve an absorbed radiation dose of 44 Gy to the 2-cm SCRC margin consistently. Our ongoing trial, as well as planned multi-institutional, randomized phase III studies in both newly diagnosed and patients with recurrent disease, will incorporate patient-specific dosimetry planning and ¹³¹I-m81C6 dosing, as well as standardized chemotherapy.³⁵

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Darell D. Bigner Abgenix (B)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: David A. Reardon, R. Edward Coleman, Henry S. Friedman, James E. Herndon II, James M. Provenzale, Michael A. Badruddoja, Michael R. Zalutsky, Darell D. Bigner Provision of study materials or patients: David A. Reardon, R. Edward Coleman, Allan H. Friedman, Henry S. Friedman, Charles N. Pegram, Jennifer A. Quinn, James J. Vredenburgh, Annick Desjardins, Terence Z. Wong, Michael R. Zalutsky, Darell D. Bigner Collection and assembly of data: David A. Reardon, Gamal Akabani, Roger E. McLendon, Jennifer A. Quinn, Jeremy N. Rich, Michael A. Badruddoja, Xiao-Guang Zhao Data analysis and interpretation: David A. Reardon, Henry S. Friedman, James E. Herndon II, Jeremy N. Rich, Jeanette M. Dowell, Darell D. Bigner Manuscript writing: David A. Reardon, James E. Herndon II, James M. Provenzale, Sri Guruangan, Michael R. Zalutsky, Darell D. Bigner Final approval of manuscript: David A. Reardon, Gamal Akabani, R. Edward Coleman, Allan H. Friedman, Henry S. Friedman, James E. Herndon II, Roger E. McLendon, Charles N. Pegram, James M. Provenzale, Jennifer A. Quinn, Jeremy N. Rich, James J. Vredenburgh, Annick Desjardins, Sri Guruangan, Jeanette M. Dowell, Terence Z. Wong, Michael R. Zalutsky, Darell D. Bigner

 

	NOTES

 
Supported by National Institutes of Health Grants No. 1-P50-CA108786-01, NS20023 and CA11898 and by Grant No. MO1 RR 30 through the General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
1. Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005[Abstract/Free Full Text]

2. Wong ET, Hess KR, Gleason MJ, et al: Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572-2578, 1999[Abstract/Free Full Text]

3. Gaspar LE, Fisher B, Macdonald DR, et al: Supratentorial malignant glioma: Patterns of recurrence and implications for external beam local treatment. Int J Radiat Oncol Biol Phys 24:55-57, 1992[Medline]

4. Bigner DD, Brown M, Coleman RE, et al: Phase I studies of treatment of malignant gliomas and neoplastic meningitis with 131I-radiolabeled monoclonal antibodies anti-tenascin 81C6 and anti-chondroitin proteoglycan sulfate Me1-14 F (ab')2: A preliminary report. J Neurooncol 24:109-122, 1995[CrossRef][Medline]

5. Bigner DD, Brown MT, Friedman AH, et al: Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: Phase I trial results. J Clin Oncol 16:2202-2212, 1998[Abstract]

6. Cokgor I, Akabani G, Kuan CT, et al: Phase I trial results of iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with newly diagnosed malignant gliomas. J Clin Oncol 18:3862-3872, 2000[Abstract/Free Full Text]

7. Reardon DA, Akabani G, Coleman RE, et al: Phase II trial of murine (131)I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas. J Clin Oncol 20:1389-1397, 2002[Abstract/Free Full Text]

8. Ventimiglia JB, Wikstrand CJ, Ostrowski LE, et al: Tenascin expression in human glioma cell lines and normal tissues. J Neuroimmunol 36:41-55, 1992[CrossRef][Medline]

9. Zalutsky MR, Moseley RP, Coakham HB, et al: Pharmacokinetics and tumor localization of 131I-labeled anti-tenascin monoclonal antibody 81C6 in patients with gliomas and other intracranial malignancies. Cancer Res 49:2807-2813, 1989[Abstract/Free Full Text]

10. Bourdon MA, Matthews TJ, Pizzo SV, et al: Immunochemical and biochemical characterization of a glioma-associated extracellular matrix glycoprotein. J Cell Biochem 28:183-195, 1985[CrossRef][Medline]

11. Bourdon MA, Wikstrand CJ, Furthmayr H, et al: Human glioma-mesenchymal extracellular matrix antigen defined by monoclonal antibody. Cancer Res 43:2796-2805, 1983[Abstract/Free Full Text]

12. Bourdon MA, Coleman RE, Blasberg RG, et al: Monoclonal antibody localization in subcutaneous and intracranial human glioma xenografts: Paired-label and imaging analysis. Anticancer Res 4:133-140, 1984[Medline]

13. Colapinto EV, Lee YS, Humphrey PA, et al: The localisation of radiolabelled murine monoclonal antibody 81C6 and its Fab fragment in human glioma xenografts in athymic mice. Br J Neurosurg 2:179-191, 1988[Medline]

14. Lee YS, Bullard DE, Wikstrand CJ, et al: Comparison of monoclonal antibody delivery to intracranial glioma xenografts by intravenous and intracarotid administration. Cancer Res 47:1941-1946, 1987[Abstract/Free Full Text]

15. Lee YS, Bullard DE, Zalutsky MR, et al: Therapeutic efficacy of antiglioma mesenchymal extracellular matrix 131I-radiolabeled murine monoclonal antibody in a human glioma xenograft model. Cancer Res 48:559-566, 1988[Abstract/Free Full Text]

16. Brem H, Piantadosi S, Burger PC, et al: Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas: The Polymer-Brain Tumor Treatment Group. Lancet 345:1008-1012, 1995[CrossRef][Medline]

17. US Food and Drug Administration: Point to consider in the manufacture and testing of monoclonal antibody products for human use. US Food and Drug Administration, 1987

18. Akabani G, Reist CJ, Cokgor I, et al: Dosimetry of 131I-labeled 81C6 monoclonal antibody administered into surgically created resection cavities in patients with malignant brain tumors. J Nucl Med 40:631-638, 1999[Abstract/Free Full Text]

19. Larson DA, Suplica JM, Chang SM, et al: Permanent iodine 125 brachytherapy in patients with progressive or recurrent glioblastoma multiforme. Neuro-oncol 6:119-126, 2004[Abstract]

20. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef]

21. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline]

22. Cox D: Regression models and life tables. J R Stat Soc B 34:187-220, 1972

23. Flickinger JC, Loeffler JS, Larson DA: Stereotactic radiosurgery for intracranial malignancies. Oncology 8:81-86, 1994 (discussion 86, 94, 97-98)

24. Gutin PH, Prados MD, Phillips TL, et al: External irradiation followed by an interstitial high activity iodine-125 implant "boost" in the initial treatment of malignant gliomas: NCOG study 6G-82-2. Int J Radiat Oncol Biol Phys 21:601-606, 1991[Medline]

25. Koot RW, Maarouf M, Hulshof MC, et al: Brachytherapy: Results of two different therapy strategies for patients with primary glioblastoma multiforme. Cancer 88:2796-2802, 2000[CrossRef][Medline]

26. Laperriere NJ, Leung PM, McKenzie S, et al: Randomized study of brachytherapy in the initial management of patients with malignant astrocytoma. Int J Radiat Oncol Biol Phys 41:1005-1011, 1998[CrossRef][Medline]

27. Loeffler JS, Alexander E III, Wen PY, et al: Results of stereotactic brachytherapy used in the initial management of patients with glioblastoma. J Natl Cancer Inst 82:1918-1921, 1990[Abstract/Free Full Text]

28. Masciopinto JE, Levin AB, Mehta MP, et al: Stereotactic radiosurgery for glioblastoma: A final report of 31 patients. J Neurosurg 82:530-535, 1995[Medline]

29. Scharfen CO, Sneed PK, Wara WM, et al: High activity iodine-125 interstitial implant for gliomas. Int J Radiat Oncol Biol Phys 24:583-591, 1992[Medline]

30. Shrieve DC, Alexander E III, Wen PY, et al: Comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme. Neurosurgery 36:275-284, 1995[Medline]

31. Sneed PK, Lamborn KR, Larson DA, et al: Demonstration of brachytherapy boost dose-response relationships in glioblastoma multiforme. Int J Radiat Oncol Biol Phys 35:37-44, 1996[CrossRef][Medline]

32. Videtic GM, Gaspar LE, Zamorano L, et al: Use of the RTOG recursive partitioning analysis to validate the benefit of iodine-125 implants in the primary treatment of malignant gliomas. Int J Radiat Oncol Biol Phys 45:687-692, 1999[CrossRef][Medline]

33. Wen PY, Alexander E III, Black PM, et al: Long term results of stereotactic brachytherapy used in the initial treatment of patients with glioblastomas. Cancer 73:3029-3036, 1994[CrossRef][Medline]

34. Yung WK, Albright RE, Olson J, et al: A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 83:588-593, 2000[CrossRef][Medline]

35. Reardon DA, Akabani G, Friedman AH, et al: Phase II study of 131-iodine-labeled antitenascin murine monoclonal antibody 81C6 (M81C6) administered to deliver a targeted radiation boost dose of 44 Gy to the surgically created cystic resection cavity perimeter in the treatment of patients with newly diagnosed primary and metastatic brain tumors, in Bigner DD (ed): Ninth Annual Meeting of the Society of Neuro-Oncology. Toronto, Ontario, Canada, Duke University Press, 2004, p 381

Submitted July 11, 2005; accepted October 14, 2005.

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				M. R. Zalutsky, D. A. Reardon, G. Akabani, R. E. Coleman, A. H. Friedman, H. S. Friedman, R. E. McLendon, T. Z. Wong, and D. D. Bigner Clinical Experience with {alpha}-Particle Emitting 211At: Treatment of Recurrent Brain Tumor Patients with 211At-Labeled Chimeric Antitenascin Monoclonal Antibody 81C6 J. Nucl. Med., January 1, 2008; 49(1): 30 - 38. [Abstract] [Full Text] [PDF]

				K. Kramer, J. L. Humm, M. M. Souweidane, P. B. Zanzonico, I. J. Dunkel, W. L. Gerald, Y. Khakoo, S. D. Yeh, H. W. Yeung, R. D. Finn, et al. Phase I Study of Targeted Radioimmunotherapy for Leptomeningeal Cancers Using Intra-Ommaya 131-I-3F8 J. Clin. Oncol., December 1, 2007; 25(34): 5465 - 5470. [Abstract] [Full Text] [PDF]

				P. L. Jones Move On!: Smooth Muscle Cell Motility Paired Down Circ. Res., March 30, 2007; 100(6): 757 - 760. [Full Text] [PDF]

				G. Wu, W. Yang, R. F. Barth, S. Kawabata, M. Swindall, A. K. Bandyopadhyaya, W. Tjarks, B. Khorsandi, T. E. Blue, A. K. Ferketich, et al. Molecular Targeting and Treatment of an Epidermal Growth Factor Receptor-Positive Glioma Using Boronated Cetuximab Clin. Cancer Res., February 15, 2007; 13(4): 1260 - 1268. [Abstract] [Full Text] [PDF]

				R. Chapados, K. Abe, K. Ihida-Stansbury, D. McKean, A. T. Gates, M. Kern, S. Merklinger, J. Elliott, A. Plant, H. Shimokawa, et al. ROCK Controls Matrix Synthesis in Vascular Smooth Muscle Cells: Coupling Vasoconstriction to Vascular Remodeling Circ. Res., October 13, 2006; 99(8): 837 - 844. [Abstract] [Full Text] [PDF]

				R. M. Sharkey Radioimmunotherapy Against the Tumor Vasculature: A New Target? J. Nucl. Med., July 1, 2006; 47(7): 1070 - 1074. [Full Text] [PDF]

				R. M. Sharkey and D. M. Goldenberg Targeted Therapy of Cancer: New Prospects for Antibodies and Immunoconjugates CA Cancer J Clin, July 1, 2006; 56(4): 226 - 243. [Abstract] [Full Text] [PDF]

				W. Yang, R. F. Barth, G. Wu, S. Kawabata, T. J. Sferra, A. K. Bandyopadhyaya, W. Tjarks, A. K. Ferketich, M. L. Moeschberger, P. J. Binns, et al. Molecular Targeting and Treatment of EGFRvIII-Positive Gliomas Using Boronated Monoclonal Antibody L8A4. Clin. Cancer Res., June 15, 2006; 12(12): 3792 - 3802. [Abstract] [Full Text] [PDF]

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