Halperin7e_CH29

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C H A P T E R 2 9  Radioimmunotherapy and Unsealed Radionuclide Therapy

for treating glioblastoma in the de novo (phase III) and recur- rent setting (phase II). Because of lack of funding, the trials were discontinued in 2010. Cotara (Peregrine Pharmaceuticals) is a 131 I-chTNT-1/B mAb used to treat high-grade glioma that is continuously instilled into the SCRC with positive pressure, using a tech- nology termed convection-enhanced delivery (CED). 70 A phase II trial was performed treating high-grade glioma (37 recur- rent glioblastomas, 8 de novo glioblastomas, 6 recurrent ana- plastic astrocytomas). The Cotara infusions delivered between 90% and 110% of the prescribed activity with an acceptable safety profile. 71 A phase III trial is pending collaboration with a funding partner. Initial promising investigations evaluated the long-term survival of patients with advanced ovarian cancer treated with RIT following cytoreductive surgery and platinum-based chemotherapy. 72 Eligibility criteria included patients with histologic evidence of ovarian cancer from stage IC to IV. The conclusion of this study was that a substantial propor- tion of patients who achieve a CR with conventional therapy can achieve a long-term survival benefit if treated with IP 90 Y-HMFG1. A phase III study was subsequently performed. 73 This multinational (74 centers, 17 countries, recruiting patients between 1998 and 2003), open-label, randomized phase III study compared 90 Y-HMFG1 (against the MUC 1 antigen) plus standard treatment versus standard treatment alone in patients with epithelial ovarian cancer (EOC) who had attained a complete clinical remission after cytoreductive surgery and platinum-based chemotherapy. Stage IC to stage IV patients were screened ( n = 844), of whom 447 with a neg- ative second-look laparoscopy (SLL) were randomly assigned to receive either a single dose of 90 Y-HMFG1 plus standard treatment (224 patients) or standard treatment alone (223 patients). Patients in the active treatment (RIT) arm received an IP dose of 25 mg 90 Y-HMFG1 to provide 666 MBq (18 mCi)/ m 2 . After a median follow-up of 3.5 years, 70 patients had died in the active treatment arm compared with 61 patients in the control arm. Cox proportional hazards analysis of sur- vival demonstrated no difference between treatment arms. In the RIT arm, 104 patients experienced relapse compared with 98 patients in the standard treatment arm. No dif- ference in time to relapse was observed between the two study arms. The conclusion was that a single IP administra- tion of 90 Y-HMFG1 to patients with EOC, who had a nega- tive SLL after primary therapy, did not extend survival or time to relapse. The reason for failure of the treatment could perhaps be explained by the choice of radionuclide. When treating microscopic disease with high-energy β -particles emitted from 90 Y, the electron will have too long of a range to deliver high enough energy to the tumor cell nuclei. It has been modeled that high-energy β -particle emissions will not deposit large amounts of energy (absorbed dose) into tumor spheroids below a certain size. However, there were other concerns about this study and these have been extensively reviewed. 74 The patterns-of-failure analysis was eventually per- formed. 75 A total of 447 patients were included in the analysis with a median follow-up of 3.5 years. Relapse was seen in 104 of 224 patients in the RIT arm and 98 of 223 patients in the control arm. Significantly fewer IP ( P < .05) and more extra- peritoneal ( P < .05) relapses occurred in the RIT arm. Time to IP recurrence was significantly longer ( P = .0019), and time to extraperitoneal recurrence was significantly shorter for the RIT arm ( P < .001). In a subset analysis, the impact of IP RIT on IP relapse-free survival was even greater and could only be seen in a subgroup of patients with residual disease after primary surgery. Although there was no survival ben- efit for 90 Y-HMFG1 IP instillation as consolidation treatment

for EOC, an improved control of IP disease was found, which appeared to be offset by increased extraperitoneal recur- rences. It was proposed that the transient myelosuppression (alteration of the immune system) induced by therapy with 90 Y-HMFG1 indirectly caused the greater number of extra- peritoneal metastases. Most likely, this observation is simply the result of an alteration in the failure pattern owing to a greater number of patients in the treatment arm benefiting from a greater IP control, as distant metastases will not be observed because of overwhelming local symptoms. In addi- tion, for reasons mentioned previously, it is possible that the treatment arm was skewed with more advanced disease. 74 Future trials should focus on both the IP and systemic deliv- ery of RIT, using an appropriate radionuclide to target micro- scopic disease. UNSEALED RADIONUCLIDE THERAPY Unsealed radionuclide therapy (URT) refers to the medical application of radiopharmaceuticals that are not conjugated to a targeting agent and thereby localize in diseased tissue by virtue of biologic, chemical, or physical avidity. 76 These radio- nuclides are considered “unsealed” because they are not con- fined within a container that could be inserted or implanted into a tumor, as is performed with conventional brachyther- apy techniques. Because they are not conjugated to a tradi- tional targeting construct, this class of therapeutics has also been referred to as “naked” radiopharmaceuticals. Oversight for the utilization of URT is governed by the U.S. FDA. 77 Safety issues, radioactive material shipping, and licensing are reg- ulated by the U.S. Nuclear Regulatory Commission (NRC). A state may enter into an agreement with the NRC to perform its own regulation and to monitor of the use of radioactive material (agreement state), with the exception of fuel facilities and nuclear reactors. States that continue to allow monitoring by the NRC are referred to as nonagreement states. The NRC receives advice regarding radiopharmaceuticals from the Advisory Committee on the Medical Use of Isotopes (ACMUI). Regulations for the practice of nuclear medicine reside in U.S. NRC Title 10 of the Code of Federal Regulations, Parts 20 and 35. Part 20 largely governs the standards for radiation pro- tection, and Part 35 governs the medical use of radioactive material. Bone-seeking radiopharmaceuticals, used for palliation of painful bone metastases, represent one of the more common uses of URT. A few of the earlier radionuclides used for this purpose include phosphorus 32 [ 32 P], samarium 153 [ 153 Sm], and strontium 89 [( 89 )Sr]; 78 however, newer agents are being investigated and are in various stages of development. 79–85 As with RIT, the radionuclides used in the application of URT can be classified as β -, α -, and Auger emitters. Many also emit gamma radiation, which can be used for imaging and dosim- etry. The radionuclides used in URT target bone by either an intrinsic affinity (i.e., 89 Sr, radium-223 [ 223 Ra]) or by using bone-seeking phosphonate ligands attached to the radionu- clide (i.e., samarium-153 ethylene diamine tetramethylene phosphonate [ 153 Sm-EDTMP] or rhenium-188 hydroxyethyli- dene diphosphate [ 188 Re-HEDP]). 82,86 Localization properties of individual agents and the clinical circumstances involved will determine routes of administration. These agents have been delivered by IV, intra-arterial, intracavitary, intra-articular (radiosynovectomy), and direct intralesional approaches. This variability of administration has been especially true for 32 P, which has been uniquely studied using IV, oral, IP, and intra- thoracic routes. 87 The initial use of a β -emitting radioisotope for the man- agement of intractable malignant bone pain was reported in 1942. Because URT demonstrates a chemical affinity for bone, the predominant thrust of clinical investigation has

Section II