Halperin7e_CH29

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S E C T I O N I I  Techniques, Modalities, and Modifiers in Radiation Oncology

the resection margin, and 4.4% to 5.8% of the peak dose was delivered to a depth of 2 cm. Of note, NCAM is expressed on benign and malignant cells and perhaps a more tumor-spe- cific antigen would allow for greater depth of penetration. Certainly, smaller targeting constructs have been shown to penetrate to a greater depth in brain parenchyma compared to intact antibodies. 63 Using the same antibody, radiolabeled with 131 I and instilled into a SCRC, it was shown that diffusion occurred from 0.5 to 1.0 cm (single-photon emission com- puted tomography [SPECT]). The range of antibody binding to the target was 8% to 80% of total injected activity. Because the R 95 (thickness of tissue where 95% of the β energy is deposited) for 131 I is only 0.992 mm, it was concluded that a more optimal radionuclide would potentially be 90 Y with an R 95 of 5.94 mm. 64 Assuming a 2-cm SCRC and 100% binding, as much as 351 Gy could be delivered to the tumor with a single instillation of 18.2 mCi of 90 Y-ERIC-1.This calculation resulted in an impres- sive minimum tumor/whole-brain dose ratio of 140:1. Using 131 I-81C6 (antitenascin mAB), dose-limiting toxicity was reached with a single injection of 80 mCi for leptomen- ingeal disease (intrathecal delivery), 100 mCi for heavily pre- treated and recurrent glioma (into SCRC), and 120 mCi for de novo glioma (into SCRC) also receiving EBRT and chemo- therapy. 65 Using a standard, fixed, mCi dose, a wide range of absorbed doses (18 to 186 Gy) will be delivered to a depth of 2 cm beyond the SCRC margin. 66 On further analysis, an optimal dose of 44 Gy to 2 cm beyond SCRC was identified. Doses <44 Gy resulted in increased recurrence rates, and doses >44 Gy resulted in a higher rate of necrosis. A trend toward significant improvement in median survival was shown for patients receiving 40 to 48 Gy versus <40 Gy. 64 Refining the technique further, it was shown that 20 of the 21 patients could be successfully dosed to 44 Gy by varying the initial injection activity and considering the volume of the SCRC. 67 Zalutsky et al. 68 showed that a high-LET, α -emitting radioconjugate ( 211 At-ch81C6) could be safely delivered in a small cohort of glioma patients. Interestingly, histopa- thology appears to correlate with prognosis. Biopsy data from patients with a suspected recurrence, after receiving 131 I-labeled antitenascin 81C6 antibody, were analyzed. Three types of histologic patterns were evident: proliferative glioma, quiescent glioma, and negative for neoplasm. The median survival for each histopathologic pattern was 3.5, 15.0, and 27.5 months, respectively ( P < .0001). Considering total dose (EBRT plus radiolabeled antibody), patients receiving <86 Gy or >86 Gy had median survivals of 7 and 19 months, respec- tively ( P < .002). 69 A review of the major RIT CNS trials 59 indicates that the range of maximum tolerated activity is between 10 and 120 mCi. There are many variables that could potentially account for the noted range. In general, by performing dosim- etry for a given radionuclide delivery construct, a specific absorbed dose can be calculated to a predetermined depth from the SCRC margin. It has been shown that 131 I-antitenascin 81C6 can deliver 2,000, 90, and 34 Gy to the cavity interface, 1 cm depth and at 2 cm depth, respectively. 64,69 The median survival for TRT in treating glioma appears extremely favor- able when compared to other treatment approaches. For de novo lesions, the median survival range is 50.9 to 57.6 months (three studies not reaching median survival at the time of the report) for anaplastic astrocytoma and 13.4 to 35.5 months for glioblastoma. For recurrent lesions, the median survival range is 13.0 to 52.0 months (one study not reaching median survival at the time of the report) for anaplastic astrocytoma and 14.0 to 25.0 months for glioblastoma. 59 Unlike sealed source brachytherapy, there appears to be a very low rate of CNS toxicity and a reduced subsequent need for surgical intervention to remove necrotic areas. Building upon Duke University research, Bradmer Pharmaceuticals developed two clinical trials using the 131 I-antitenascin antibody (Neuradiab)

inositide. The EGFR is variably amplified in malignant tissue and is also present, to some extent, in benign tissue. Tenascin is an extracellular glycoprotein that is uniformly expressed in glioma, and NCAM is present on both benign and malignant glioma cells. Clinical trials using RIT to treat CNS malignan- cies have been extensively reviewed. 59 A phase III trial was reported in 2002. 60 A total of 12 patients with malignant gli- oma were randomized to surgical resection and radiotherapy (60 Gy) ( n = 5) versus surgical resection, radiotherapy, and RIT ( n = 7). The RIT agent was a 125 I-anti–EGFR antibody 425 that was administered intravenously in three weekly doses (50 mCi) beginning during week 4 of the EBRT. All patients in the treatment arm had a recurrence at the time of publi- cation. Considering that the EGFR was not tested in submit- ted tissue, the trial had a small number of patients, and the 150-kDa antibody was administered intravenously, significant conclusions could not be drawn. Most of the CNS RIT trials to date are of “dose searching pilot” or phase I design. The evolution of the trials has seen the delivery route move from systemic (intra-arterial or IV) to local instillation of the RIT agent into a surgically created resection cavity (SCRC). Even though the blood–brain barrier (BBB) is often disrupted by a rapidly growing CNS malignancy, this phenomenon is not well defined, and 150-kDa antibodies would still not likely cross to a significant degree, although there does appear to be an element of nonspecific uptake from a systemic delivery. As a result, studies using the sys- temic approach often deliver EBRT in conjunction with TRT. It has been well documented that EBRT will cause an increase in the permeability of the BBB and increase vascular leakage. Regardless, it has been disappointingly estimated that only 0.001% to 0.01% of the systemically delivered antibody will penetrate each gram of solid tumor. Furthermore, biopsy data have revealed that a single systemic injection of radiolabeled anti-EGFR antibody will deliver only 0.02% of the injected activity per gram of tumor, resulting in a dose of only 100 to 200 cGy. Direct instillation of the TRT agent into the SCRC is an attractive alternative to the systemic approach. Unlike other malignant sites where the potential for systemic spread man- dates a systemic approach, this is not the case for malignant gliomas. The local approach is accomplished by injecting or instilling the RIT agent directly into the SCRC via an Ommaya or Rickham catheter. Preliminary dosimetry is performed to ensure localization within the surgical bed and that no direct communication with the ventricular system has occurred. Institutions using this technique have utilized murine, chime- ric, or humanized mAbs attached to 131 I, 90 Y, 188 Re, and 211 At. Other important treatment variances include fractionation, pretargeting, and a combined modality approach using EBRT and chemotherapy. The success of this approach will depend on meaningful penetration of the RIT agent into the local brain parenchyma such that the mAbs (or targeting construct) can bind to areas of microscopic extension of malignant cells at some distance from the SCRC margin. It is still unknown as to what impact the healing process/inflammation at the sur- gical margin has on the success of antibody penetration. As well, it is well known that binding site barrier phenomena, interstitial tumor pressure, aberrant tumor vasculature, and a recusant extracellular tumor matrix will significantly impede antibody penetration. 61 Hopkins et al. 62 obtained biopsy data from three patients with glioma who received two to three cycles of either 131 I or 90 Y-ERIC-1 (anti-NCAM antibody) directly instilled into a SCRC. Relevant assumptions were that the SCRCs were spherical, the radionuclide was spread evenly around the resection mar- gin, 100% of the RIT agent was bound to its target, and diffu- sion into the resection margin was uniform. It was shown that “modest” diffusion occurred and the process was exponential. The peak dose occurred between 0.16 and 0.18 cm beyond