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© 2002 American Society for Clinical Oncology Phase II Trial of Murine 131I-Labeled Antitenascin Monoclonal Antibody 81C6 Administered Into Surgically Created Resection Cavities of Patients With Newly Diagnosed Malignant GliomasByFrom the Departments of Surgery, Medicine, Pathology, Radiology, and Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC; and Department of Medicine, University of California at Davis Medical Center, San Rafael, CA. Address reprint requests to David A. Reardon, MD, Department of Surgery, Division of Neurosurgery, Duke University Medical Center, Box 3624, Durham, NC, 27710; email: reard003{at}mc.duke.edu
PURPOSE: To assess the efficacy and toxicity of intraresection cavity 131I-labeled murine antitenascin monoclonal antibody 81C6 and determine its true response rate among patients with newly diagnosed malignant glioma. PATIENTS AND METHODS: In this phase II trial, 120 mCi of 131I-labeled murine 81C6 was injected directly into the surgically created resection cavity of 33 patients with previously untreated malignant glioma (glioblastoma multiforme [GBM], n = 27; anaplastic astrocytoma, n = 4; anaplastic oligodendroglioma, n = 2). Patients then received conventional external-beam radiotherapy followed by a year of alkylator-based chemotherapy. RESULTS: Median survival for all patients and those with GBM was 86.7 and 79.4 weeks, respectively. Eleven patients remain alive at a median follow-up of 93 weeks (range, 49 to 220 weeks). Nine patients (27%) developed reversible hematologic toxicity, and histologically confirmed, treatment-related neurologic toxicity occurred in five patients (15%). One patient (3%) required reoperation for radionecrosis. CONCLUSION: Median survival achieved with 131I-labeled 81C6 exceeds that of historical controls treated with conventional radiotherapy and chemotherapy, even after accounting for established prognostic factors including age and Karnofsky performance status. The median survival achieved with 131I-labeled 81C6 compares favorably with either 125I interstitial brachy-therapy or stereotactic radiosurgery and is associated with a significantly lower rate of reoperation for radionecrosis. Our results confirm the efficacy of 131I-labeled 81C6 for patients with newly diagnosed malignant glioma and suggest that a randomized phase III study is indicated.
IMPROVEMENT IN outcome for patients with the most common primary adult brain tumor, malignant glioma, has been elusive despite more than two decades of intensive clinical and laboratory research. In particular, outcome for patients with glioblastoma multiforme (GBM) remains unacceptable, with the median survival for patients with newly diagnosed GBM and recurrent GBM being only 40 to 601 and 16 to 24 weeks, respectively.2 Failure to eradicate local tumor growth is a major factor contributing to poor outcome, as indicated by the development of 90% of GBM recurrences at or adjacent to the site of origin.3 Therefore, adjuvant therapies designed to augment local control are critically needed. The delivery of chemotherapeutic agents, toxins, or radionuclides to tumor-associated antigens via monoclonal antibodies (mAbs) is one such approach. Our efforts have focused on administering tumor-associated radiolabeled mAbs directly into spontaneous tumor cysts, surgically created resection cavities (SCRCs), the intrathecal space, and solid tumors.4-6 Tenascin, an extracellular matrix hexabrachion glycoprotein, is expressed ubiquitously in high-grade gliomas and in breast, lung, and squamous cell carcinomas, but not in normal brain. mAb 81C6 is a murine immunoglobulin G2b that binds an epitope within the alternatively spliced fibronectin Type III region of tenascin.7,8 This tenascin isoform is abundantly expressed in gliomas.9,10 Preclinical studies have confirmed the specificity of 81C6 for tenascin-expressing tumors in cell culture and xenograft model systems. Bourdon et al11 first demonstrated preferential localization of radioiodinated antitenascin 81C6 mAb in subcutaneous and intracranial human xenografts in athymic mice and rats using paired-label analysis. Additional preclinical studies with 131I-labeled 81C6 demonstrated significant tumor growth delay and regression in athymic mice bearing subcutaneous D-54/MG human glioma xenografts and prolongation of median survival for athymic rats bearing intracranial tumors.12-14 These promising results in preclinical animal studies led to a paired-label study in humans with recurrent malignant glioma. In this study, biopsy specimens obtained after intravenous injection of 123I-labeled 81C6 demonstrated tumor-to-normal brain ratios up to 25:1 and single photon emission computed tomography localization indices showed an up to five-fold higher tumor accumulation of 81C6 compared with control immunoglobulin G2b murine immunoglobulin.15 We have performed a series of phase I clinical trials to establish the maximum-tolerated dose (MTD) of 131I-labeled murine 81C6 (mu81C6) mAb injected directly into a patient’s SCRC. The MTD for three subgroups of patients with CNS tumors was established by the following studies: (1) 80 mCi for adult patients with leptomeningeal neoplasms or brain tumor resection cavities that communicate with the subarachnoid space,4 (2) 100 mCi for patients with recurrent malignant gliomas who received prior radiation therapy with or without chemotherapy,5 and (3) 120 mCi for newly diagnosed and previously untreated adult patients with malignant gliomas.6 In the latter group, delayed neurologic toxicity was dose-limiting and the median survival for all patients and those with GBM was 79 and 69 weeks, respectively. We now report the results of a phase II study using 120 mCi of 131I-labeled mu81C6 mAb injected directly into the SCRCs of newly diagnosed and previously untreated adult patients with malignant gliomas.
Patient Eligibility and Treatment Eligible patients had a confirmed histologic diagnosis of a newly diagnosed, previously untreated, supratentorial primary malignant tumor and were candidates for surgical resection. Patients with tumors that were either infratentorial, diffusely infiltrating, or multifocal or that had intraventricular access or subependymal spread were not eligible. Histopathologic samples from initial surgery for all patients were centrally reviewed at Duke University Medical Center (R.E.M., Department of Pathology, Durham, NC), and we performed a test of immunoreactivity for tenascin using either fresh or paraffin-embedded tissue stained positively with 81C6 or affinity-purified polyclonal rabbit antitenascin serum, respectively. Patients were greater than 3 years of age and had a Karnofsky performance status (KPS) of at least 60% at study entry. Pregnant or lactating patients and those with iodine allergy were ineligible. Concurrent systemic chemotherapy was not allowed. Other requirements have been described previously.4 Patients underwent a gross total resection and placement of a Rickham reservoir and catheter into the SCRC. A magnetic resonance imaging (MRI) scan with contrast was obtained within 48 hours of resection to document any residual tumor and placement of the Rickham catheter. Residual tumor could not enhance measurably more than 1.0 cm beyond the margin of the SCRC. Patency of the Rickham catheter and intactness of the SCRC were confirmed by injecting technetium-99m (99mTc)-labeled albumin or diethylenetriamine pentaacetic acid into the Rickham reservoir and obtaining gamma camera images immediately, 4 hours, and 24 hours after injection. Patients with subgaleal leakage of 99mTc-labeled tracer from the SCRC or with a resection cavity that communicated with the subarachnoid space (ie, intrathecal communication) were not eligible for treatment on this protocol. A baseline [18F]fluorodeoxyglucose positron emission tomography (18FDG PET) scan was obtained after resection. Before and 30 to 120 days after treatment, patients were tested for circulating antibodies to mu81C6 antibody and human-mouse chimeric 81C6 (ch81C6) antibody constructs with a double antibody radioimmunoassay or an enzyme-linked immunoabsorbent assay.4 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-labeled 81C6 mAb administration to decrease iodine accumulation to the thyroid. After a patient was admitted to the hospital, the Rickham reservoir was accessed with a 25-gauge butterfly needle using sterile technique. Cystic fluid up to a volume of 6 mL was removed when possible. Twenty milligrams of 81C6 mAb labeled with 120 mCi of 131I was injected into the reservoir in a volume of 6 mL or less. The reservoir and catheter were flushed after the mAb injection. Patients were placed on radiation isolation until the whole-body retention of 131I was less than 30 mCi, as determined with a cross-calibrated radiation survey meter. After this level was reached, radionuclide imaging with a gamma camera and serial blood sample measurements were performed to document the biodistribution of 131I activity in the whole body. Patients were discharged after a posttreatment MRI was performed. The Duke Investigational Review Board approved this investigation. Informed consent approved by the Duke Investigational Review Board was obtained from each subject or the subject’s guardian.
Antibody Production and Labeling
Pharmacokinetics and Dosimetry
Toxicity and Response Determinations Common toxicity criteria, version 2.0 (Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD), was used to score toxicity. Although the occurrence of seizures was recorded, seizures were not included as an indication of neurologic toxicity because of their expected frequency in this disease setting. The precise etiology of nonseizure neurologic toxicity after 131I-labeled 81C6 therapy was extremely difficult to define. Neither clinical features nor radiographic findings observed on either MRI or 18FDG PET scan reliably distinguished between recurrent tumor and treatment-induced radiation necrosis. Although stereotactic needle biopsy is limited with regard to volume sampling, it remains the state of the art for diagnosis of focal brain lesions. Therefore, the etiology of observed neurologic toxicity was determined based on stereotactic needle biopsy result. Progressive disease (PD) was defined by the presence of at least one of the following: (1) more than 25% increase in the enhancing tumor cross-sectional area or the appearance of radiographically new lesions that were also hypermetabolic on 18FDG PET scan, (2) evidence of clinical deterioration and a more than 25% increase in enhancing tumor size or the appearance of radiographically new lesions on MRI, or (3) biopsy-proven recurrent tumor.
Statistical Analysis The method of Kaplan and Meier19 was used to estimate survival distributions, where survival was measured from the date of initial treatment to the date of death or last contact. Subgroup differences in survival were assessed with log-rank tests,20 and the Cox Proportional Hazards Model21 was also used to investigate for potential associations between variables and outcome. Logistic regression was used to examine the effect of cavity size as well as 131I-labeled 81C6 absorbed and cumulative (131I-labeled 81C6 plus external beam) radiation doses to the 2 cm-thick SCRC interface on toxicity. This analysis reflects patient follow-up through May 15, 2001.
Patient Characteristics The study population included 33 previously untreated patients with newly diagnosed high-grade glioma treated at Duke University Medical Center. Study accrual began in November 1996 and was discontinued in June 2000 once it became clear that the treatment regimen was worthy of further investigation in a phase III study (ie, 21 or more successes were observed) and ch81C6 became available for clinical use. Subsequent patients were enrolled onto a phase I clinical trial incorporating ch81C6 because it was shown to demonstrate superior tumor localization in paired label studies of human glioma xenografts and greater overall stability compared with mu81C6.22 Characteristics of the patients enrolled onto the current study are listed in Table 1. Ten of the patients were women, and 23 were men. The median age was 50 years (range, 19 to 68 years). Twenty-seven of the patients had GBM, four had AA, and two had anaplastic oligodendroglioma (AO). All patients had a KPS between 70% and 100%. The median time between diagnosis and 131I-labeled 81C6 administration was 1.3 months (range, 1 to 3 months). Thirty-two patients received 120 mCi of 131I conjugated to 20 mg of 81C6 mAb. One patient received 37 mCi of 131I conjugated to 10 mg of 81C6 mAb because of a small SCRC. After 131I-labeled 81C6 therapy, 29 patients underwent conventional external-beam radiation therapy, and 30 received systemic chemotherapy. There are 11 patients currently alive. Median follow-up among surviving patients is 93 weeks (range, 49 to 220 weeks). Twenty-two patients have died.
HAMA Immunoassays were performed for HAMA to assess the patients’ immune response to mu81C6 and ch81C6 antibody and to determine any HAMA-associated toxicity. Posttreatment blood samples were obtained from 31 patients within 1 to 6 months after treatment. When tested against the target immunoglobulin, 25 (86%) of 29 patients were positive for mu81C6, and 27 (90%) of 30 were positive for ch81C6. The maximum titer measured from each patient is presented in Table 2. No observed toxicity was related to HAMA reactivity.
Dosimetry Results As demonstrated in previous studies, retention of the 131I-labeled 81C6 in the SCRC and in the whole body differed significantly.6 131I activity in the blood was characterized by exponential uptake followed by an exponential clearance. Overall, patients remained in radiation isolation for 3 to 8 days until adequate clearance was achieved. The average biologic half-life in the SCRC and in the whole body was 87 hours (range, 26 to 282 hours) and 39 hours (range, 8 to 66 hours), respectively. The average SCRC volume was 10.45 cm3 (range, 0.5 to 30.5 cm3). The average absorbed dose to the 2 cm-thick interface from 131I-labeled 81C6 was 48 Gy (range, 24 to 116 Gy), with an average SCRC residence time of 78 hours (range, 34 to 169 hours). The average cumulative radiation dose to the 2 cm-thick interface (external-beam radiation therapy plus 131I-labeled 81C6 absorbed dose) was 102 Gy (range, 51 to 137 Gy). The average whole-body dose was 0.58 Gy (range, 0.24 to 1.28 Gy), with an average whole-body residence time (excluding the SCRC) of 40 hours (range, 12 to 89 hours).
Toxicity
Three patients (3%) developed neurologic toxicity (grade Two additional patients developed irreversible neurologic toxicity and refused stereotactic biopsy. However, clinical and radiographic findings clearly suggested that progressive tumor was responsible for their neurologic decline. The first patient developed grade 4 neuromotor and cognitive deficits 20 weeks after 131I-labeled 81C6 therapy, at which point MRI examination revealed a new enhancing lesion separate from the original tumor that was also hypermetabolic on 18FDG PET scan. This patient’s course was remarkable for progressive worsening of neurologic and radiographic findings, and he died on hospice care 88 weeks after 131I-labeled 81C6 therapy. The second patient developed grade 3 cognitive toxicity 5 weeks after 131I-labeled 81C6 therapy. At that time, his MRI examination revealed enhancement extending into the corpus callosum. He also developed progressive neurologic deterioration and died 20 weeks after 131I-labeled 81C6 therapy. New onset, controllable seizures developed in four patients (12%) after 131I-labeled mu81C6 therapy. One of the four patients had biopsy-proven PD at the onset of seizures, whereas biopsy samples were not obtained from the remaining three patients. Worsening of pre-existing seizures occurred primarily in the setting of tumor progression.
Other episodes of reversible grade
Biopsies and Reoperation
Response/Survival Data
Eleven (33%) of the 33 patients are alive, including three of six with AA or AO and eight of 27 with GBM. The median survival after 131I-labeled 81C6 therapy for all patients (Fig 1A) and the 27 patients with GBM (Fig 1B) was 86.7 weeks (95% confidence interval, 76.7 to
The primary objective of the current phase II study was to assess the impact on survival of 120 mCi of 131I-labeled mu81C6 administered directly into the SCRC of newly diagnosed and previously untreated patients with malignant glioma. Our secondary objective was to further assess the feasibility and toxicity associated with this therapy among such patients. Overall, 33 patients were treated, including 27 with GBM, four with AA, and two with AO. The most eligible patients were enrolled onto the study and received 131I-81C6; however, a small percentage were ultimately excluded because of subgaleal leakage on the postoperative diethylenetriamine penta-acetic acid scan. A review of the last 36 consecutive patients meeting this study’s eligibility criteria revealed that three (8%) were excluded for this reason. Of note, this development seemed to be related to the proximity of the SCRC to the CSF space rather than SCRC size. In fact, the SCRC of all three of these patients was less than 5 cm3. After administration of 131I-labeled 81C6 mAb, most patients received conventional external-beam radiotherapy followed by a year of alkylator-based chemotherapy. The average SCRC volume in this study was 10.45 cm3 (range, 0.5 to 30.5 cm3), and the average radiation absorbed dose to the 2 cm-thick region surrounding the cavity interface was 48 Gy (range, 24 to 116 Gy). Median survival was 86.7 weeks (range, 76.7 to  weeks) for all patients and 79.4 weeks (range, 61.4 to weeks) for those with GBM. Toxicity was primarily hematologic and neurologic, as predicted by our prior phase I study. Reversible grade 4 hematologic toxicity developed in nine patients (27%). Neurologic toxicity occurred primarily in the setting of PD documented by either biopsy or radiographic findings. However, five patients (15%) developed grade  3 irreversible neurologic toxicity without evidence of tumor recurrence on stereotactic biopsy. The results of prior phase I clinical trials contributed to the design and implementation of the current study. In our initial phase I trial, 31 patients (18 with GBM) with either leptomeningeal neoplasms or brain tumor resection cavities with subarachnoid communication were treated with a single dose of intrathecal 131I-labeled mu81C6.23 Iodine-131 doses administered to patients ranged from 40 to 100 mCi. Hematologic dose-limiting toxicity correlated with 131I dose and occurred at an absorbed dose to active bone marrow of approximately .20 Gy. No grade III or IV nonhematologic toxicity was encountered. One patient had a partial response, whereas 13 (42%) of 31 had disease stabilization. Twelve patients were alive (median follow-up > 320 days) and five were progression-free more than 409 days median after treatment. From this study, we concluded that 80 mCi of 131I-labeled 81C6 was the MTD when administered as a single intrathecal administration in adults. In a subsequent phase I study, 34 previously irradiated patients with recurrent or metastatic brain tumors (26 with GBM) received a single injection of 131I-labeled mu81C6 through an Ommaya reservoir into the SCRC.5 Administered doses of 131I-labeled 81C6 ranged from 20 to 120 mCi. Dose-limiting toxicity was neurologic and defined the MTD to be 100 mCi for recurrent patients. The estimated median survival for those patients with recurrent GBM and for all patients was 56 and 60 weeks, respectively. In a recently reported phase I study, 42 newly diagnosed, previously untreated patients with supratentorial primary malignant glioma (32 with GBM) received doses of 131I-labeled mu81C6 directly into the SCRC via a Rickham catheter.6 The average SCRC volume was 21 cm3 (range, 2 to 81 cm3). 131I-labeled 81C6 doses ranged from 20 to 180 mCi and delivered an average 32 Gy (range, 2 to 59 Gy) to the 2 cm-thick region surrounding the cavity interface. Median survival for all patients and those with GBM was 79 and 69 weeks, respectively. Dose-limiting neurotoxicity was observed at the following administered activities: one of seven patients at 120 mCi, two of three patients at 140 mCi, two of seven patients at 160 mCi, and the sole patient treated with 180 mCi. The average absorbed dose to the 2-cm shell from radiolabeled mAb therapy for these six patients was 46 Gy (range, 37 to 55 Gy). Of note, only one of the 42 patients (2.5%) required debulking surgery for radionecrosis. Non–dose-limiting, reversible, hematologic toxicity was observed in seven patients (grade 3, n = 5; grade 4, n = 2). Based on these results, an MTD of 120 mCi was established for newly diagnosed, previously untreated patients. Presently, nine patients in that study remain alive, including all five with AO and four with GBM. Current posttreatment survivals range from 130 to 367 weeks. Median survival in the current study exceeded that observed in our previous phase I trial, thereby further defining the efficacy of 131I-labeled 81C6 administered into the SCRC of newly diagnosed malignant glioma patients. Irreversible treatment-related neurologic toxicity was associated with contiguity or immediate adjacency of the SCRC and respective functional CNS area. Specifically, each of the five patients with irreversible neuromotor toxicity in this study had an SCRC in direct proximity to the motor strip, whereas the anterior margin of the SCRC of the patient who also developed speech toxicity localized to the region of Broca’s area. In addition, it is possible that the higher average radiation dose affecting the 2-cm SCRC shell (48 Gy) compared with that achieved in the prior phase I trial (32 Gy) may have contributed to the neurologic toxicity observed in the current study. A recently completed dosimetry analysis designed to evaluate the dose-response relationship observed in our previous phase I study suggested that a boost dose of 43 Gy to the 2-cm SCRC shell optimally maximized tumor control and minimized brain injury. Moreover, 2-cm SCRC shell doses greater than 43 Gy were more frequently associated with brain injury, and tumor recurrence occurred more frequently when 2-cm SCRC shell doses were less than 43 Gy.24
Curran et al25 used recursive partitioning to assess the prognostic impact of 26 pretreatment characteristics and six treatment-related variables for 1,578 newly diagnosed malignant glioma patients entered onto three Radiation Therapy Oncology Group trials from 1974 to 1989. They confirmed age, histopathology, and performance status to be most predictive of survival. This analysis also determined survival rates for subsets of malignant glioma patients treated with conventional chemoradiotherapy, against which outcomes using novel therapeutic approaches could be compared. Such a comparison is limited by the sample size of our study and its exclusion of patients with tumors that are either diffusely infiltrating, multifocal, or accompanied by subependymal spread, but nonetheless suggests that the use of 131I-labeled 81C6 provides a survival advantage for patients stratified by age, histology, and performance status. Median survival was 87 weeks for the 11 patients in the current study who were less than 50 years old at diagnosis and had GBM, compared with only 55 weeks for a similar cohort in the Curran et al25 analysis (P < .05). Similarly, median survival was 65 weeks for the 16 GBM patients over 50 years old with a KPS Other investigators have documented improved survival associated with the local application of radiolabeled mAbs for patients with malignant gliomas. Riva et al26,27 injected 131I-labeled antitenascin murine mAbs BC-2 and BC-4 into the resection sites of 74 newly diagnosed and recurrent glioblastoma patients in a phase II study. All patients received external-beam radiotherapy and systemic chemotherapy before mAb therapy. The mean administered activity was 2,035 MBq (approximately 55 mCi). Median survival was 76 weeks, and no neurologic toxicity was encountered. In a pilot study for patients with malignant gliomas, individual patient responses were documented after intracystic injection of 131I-labeled erythropoietin-induced c-DNA-1 murine mAb.28 Hopkins et al29 reported a median survival of 24 weeks among 15 primary brain tumor patients treated with intratumoral 90Y-labeled erythropoietin-induced c-DNA-1 murine mAb. The 79.4-week median survival for patients with GBM in the current study compares favorably with that reported for either 125I interstitial brachytherapy (IB) or stereotactic radiosurgery (SRS). Trials incorporating 125I IB report a median survival of 48 to 88 weeks for newly diagnosed malignant glioma patients,30-37 whereas those using SRS cite a 38- to 78-week median survival.38-40 However, reoperation to alleviate increasing mass effect and radiation necrosis was required in 33% to 64% of 125I IB cases and up to 33% of SRS patients. In contrast, only two (2.7%) of the 75 newly diagnosed patients combined from our phase I and II 131I-labeled 81C6 trials required debulking resections for radionecrosis. In addition, median survival achieved in the current study with 131I-labeled 81C6 exceeds the 56 weeks reported with interstitial chemotherapy using carmustine-loaded polymers (Gliadel; Guilford Pharmaceuticals Inc, Baltimore, MD) placed in the surgical resection cavity at the time of primary operation for patients with newly diagnosed malignant glioma.41 In summary, 120 mCi of 131I-labeled mu81C6 mAb injected into the SCRC of newly diagnosed and previously untreated malignant glioma patients resulted in prolonged overall survival compared with that achieved with conventional therapy or interstitial chemotherapy. Our median survival compares favorably with that reported for SRS or 125I IB, and significantly fewer patients in our study required reoperation for symptomatic radionecrosis than reported for either SRS or 125I IB. Observed hematologic toxicity and neurologic toxicity in this trial were acceptable. The latter may be further reduced by limiting 131I-labeled 81C6 mAb therapy to those patients in whom the SCRC is not immediately adjacent to critical CNS functional centers. In this regard, we have begun to routinely use intraoperative cortical mapping to further delineate such patients. Overall, these results suggest that a randomized phase III trial is warranted.
Supported by National Institutes of Health grant nos. 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, Bethesda, MD.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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