Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Immunocontraception wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Autoimmune encephalitis wikipedia , lookup
Multiple sclerosis signs and symptoms wikipedia , lookup
Management of multiple sclerosis wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Radioimmunotherapy may have applications in many solid tumors as well as in lymphomas. Nick Patten. Interior With Still Life. Oil on panel, 24ʺ × 36ʺ. The New Golden Era for Radioimmunotherapy: Not Just for Lymphomas Anymore Michael B. Tomblyn, MD, MS, Michael J. Katin, MD, and Paul E. Wallner, DO Background: Radioimmunotherapy (RIT) has been approved for the treatment of B-cell non-Hodgkin lymphomas in the United States for more than a decade. However, the history of the development of RIT agents for advanced-stage solid malignancies dates back much further, and recent advances have renewed interest in this approach for solid tumors. Methods: This paper reviews available evidence for the preclinical and clinical development of RIT agents for solid tumors. Results: Several RIT agents have been studied for the treatment of a variety of solid malignancies, particularly colorectal, breast, prostate, ovarian, pancreatic, hepatocellular, and primary brain tumors. Multiple novel RIT agents are in active clinical investigation, either as single agents or combined with radiosensitizing chemotherapy or with external beam radiotherapy. Improvements in antibody (and antibody fragment) design and the availability of novel radionuclides have improved the therapeutic window for these agents. Conclusions: RIT for solid malignancies shows promise, typically with fewer adverse events than traditional cytotoxic systemic therapy. The greatest efficacy will likely be in the adjuvant setting of minimal residual disease. Newer radionuclides, particularly alpha-emitters, offer increased antitumor potency with less toxicity. Physicians and patients should be encouraged to participate in clinical trials of these promising agents. Introduction The concept of radiolabeled antibodies targeted against tumor cells is hardly novel, having been first described in the early 1950s.1 Initially, investigators From the Department of Radiation Oncology at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida (MBT), and 21st Century Oncology, Fort Myers, Florida (MJK), and Voorhees, New Jersey (PEW). Submitted August 15, 2012; accepted October 15, 2012. Address correspondence to Michael B. Tomblyn, MD, MS, Department of Radiation Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, MCC-RAD ONC, Tampa, FL 33612. E-mail: Michael. [email protected] No significant relationship exists between the authors and the companies/organizations whose products or services may be referenced in this article. Dr Tomblyn has received research support from Immunomedics, Inc. Dr Wallner was the chair of the American Society for Radiation Oncology’s Systemic Targeted Radionuclide Therapy program. 60 Cancer Control utilized radiolabeled polyclonal antibodies from various mammalian species for radioimmunodetection and the first attempts at radioimmunotherapy (RIT).2,3 In 1975, Köhler and Milstein4 developed hybridoma techniques that paved the way to the production of monoclonal antibodies. Within a few years, early radiolabeled monoclonal antibodies were reported to eliminate melanomas in a murine model.5,6 Soon afterward, the first clinical human experiences with RIT were conducted.7 Results from many of these early clinical studies of RIT were somewhat mixed, owing to the relatively modest radiosensitivity of epithelial cancers to lowdose radiation, the heterogeneous expression of target antigens in normal tissues, and the immunogenicity of these typically murine or lupine antibodies, preventing efforts at repeat dosing. These and other fundamental challenges for RIT have been compreJanuary 2013, Vol. 20, No. 1 hensively reviewed elsewhere8 and are beyond the scope of this review. More recently, attention has turned to the development of RIT agents for the treatment of B-cell non-Hodgkin lymphomas, which are inherently radiosensitive and express antigens not typically found in normal tissue. Ibritumomab is a murine monoclonal antibody that binds to CD20, which is found on the surface of mature B cells and most B-cell malignancies. This antibody utilizes the linker-chelator tiuxetan to hold yttrium-90 (90Y), a beta-emitting radioisotope, for the purpose of RIT. However, repeat dosing with 90Y ibritumomab tiuxetan led to the development of human antimurine antibodies (HAMAs). A chimeric version of the antibody was produced — rituximab — that exhibited a significant antilymphoma effect in the absence of the radioisotope and without the development of HAMAs. In 1997, rituximab was the first monoclonal antibody to receive approval by the US Food and Drug Administration (FDA).9 During the next several years, the development of RIT agents for B-cell non-Hodgkin lymphoma continued, which led to the FDA approval of 90Y ibritumomab tiuxetan in 200210 and iodine-131 (131I) tositumomab in 2003.11 Both agents are indicated for relapsed or refractory low-grade B-cell non-Hodgkin lymphomas, while 90Y ibritumomab tiuxetan is also used in the frontline setting following at least a partial response (PR) to induction chemoimmunotherapy. Several other RIT agents for lymphomas have been investigated. Perhaps the most promising is 90Y epratuzumab tetraxetan, which is currently in clinical trials for aggressive B-cell lymphomas,12 newly diagnosed follicular lymphoma, and B-cell acute lymphoblastic leukemia (NCT01101581, NCT01147393, and NCT01354457). The role of RIT for B-cell non-Hodgkin lymphomas has recently been reviewed.13 In general, solid tumors are much less radiosensitive than B-cell lymphomas, requiring higher delivered doses for significant clinical efficacy.14 Here, we review major attempts at solid tumor RIT and emerging techniques for improving the therapeutic window of this modality in the treatment of advanced solid malignancies. Colorectal Cancer Cancer of the colon and rectum is the third most common form of malignancy in the United States, accounting for 9% of all cancer cases.15 In 2012, an estimated 143,460 new cases were diagnosed and 51,690 patients died of types of colorectal cancer (CRC).15,16 Some of the earliest RIT experiences have been in CRC, principally due to the early discovery of carcinoembryonic antigen (CEA) and tumor-associated glycoprotein 72 (TAG-72), both of which are often highly expressed in CRC tumors. Beginning in the late 1980s, investigators began to examine 131I-labeled anti-CEA antibodies and antibody fragments in xenograft models of metastatic CRC.17-20 In dosimetric studies, investigators quickly realized that the absorbed January 2013, Vol. 20, No. 1 tumor dose is inversely proportional to the radius of the tumor mass, making the treatment of bulky tumor burden impractical for RIT but promising for micrometastatic disease.21-23 Due to its early characterization and ubiquity of expression in CRC,24 CEA has been the most common target for RIT in this disease. Lane et al25 reported one of the earliest human trials of an anti-CEA radiolabeled antibody. Seventeen patients with CRC received the murine 131I-A5B7 anti-CEA antibody, either as the intact immunoglobulin (Ig)-G form or as the F(abʹ)2 fragment. This study reported 1 complete response (CR) and 1 PR. One important observation was that the smaller antibody fragments localized to tumor faster than did IgG. Another important anti-CEA antibody, neutrophil proteinase-4 (NP-4), has been extensively evaluated. A phase I/II trial of 131I-NP-4, a murine IgG1 antibody, treated 57 patients, 29 of whom had CRC.26 A single objective response was seen in the study, with 4 patients exhibiting minor responses. The same group then examined the F(abʹ)2 fragment of this antibody in a small phase I trial with 13 patients, 8 of whom had CRC.27 All patients had a relatively small burden of disease with no mass larger than 3 cm in diameter. Four patients exhibited stable disease (SD) lasting up to 7 months. MN-14 is a murine IgG monoclonal antibody against CEA with an order-of-magnitude greater affinity for the antigen than NP-4. Juweid et al28 reported the results of a phase I trial of rhenium-188 (188Re)-MN-14 in 10 patients with CRC. A fractionated approach was used due to the relatively short halflife of 188Re, with 2 or 3 divided doses given to study participants to deliver higher doses with less toxicity than that seen with a 131I-labeled antibody. The group reported a maximum tolerated dose (MTD) of 60 mCi/ m2, with the ability to deliver this on an outpatient basis. Two patients in the study developed HAMAs. The concern over the potential immunogenicity posed by treatment with murine monoclonal antibodies led to the development of a humanized version of their anti-CEA antibody, humanized MN-14 (hMN14). Two studies have been reported in patients with small-volume disease.29,30 In both studies, 16% of patients exhibited an objective response, with 42% to 45% showing a mixed or minor response to RIT. The group also performed several studies of adjuvant 131IhMN-14 following R0 resection of hepatic metastases in patients with CRC.30-33 The median disease-free survival (DFS) in these studies was approximately 18 months, with 5-year overall survival (OS) in nearly half of the treated patients. The antibody cT84.66, a chimeric IgG anti-CEA antibody against the A3 epitope of CEA, is highly selective for tumor CEA expression and binds with great affinity.34 Wong et al35-38 have published several reports on cT84.66, and several phase I studies have been performed with this 90Y-labeled antibody Cancer Control 61 in patients with CRC, with minor responses ranging from 31% to 57%. Several other murine anti-CEA RIT agents have been evaluated in early phase clinical trials, including 131I-NP-4, 131I-F6 F(abʹ)2, 131I-A5B7, 131I-COL-1, and 186Re-NR-CO-2 F(abʹ) , all with modest objective re2 sponses.39-45 CEA is not the only antigen targeted for RIT in patients with CRC. TAG-72 is another popular target with significant clinical experience. The antibody most utilized to target TAG-72 has been the murine IgG, CC49. Several groups have published their experiences with CC49, most often labeled with 131I. Divgi et al46 reported the results of a phase I trial of 24 patients treated with 131I-CC49 in which 25% of patients exhibited SD or a minor response to RIT. The MTD was reported to be 75 mCi/m2, and all patients developed HAMAs. Murray et al47 reported a similar phase II study in which followed 15 patients with CRC receiving 131I-CC49 at 75 mCi/m2. Minor responses were seen in approximately 20% of patients, and all but 1 patient developed HAMAs. Wheeler et al48 reported the results of a phase II trial of 131I-CC49 in 15 patients with CRC, using interleukin (IL)-1 in an attempt to reduce hematologic toxicity. Five 5 patients exhibited a minor response to therapy. Mulligan et al49 reported on the use of 177Lu-CC49 and found 15 mCi/ m2 to be the MTD. In that study, 2 patients showed a minor response. Divgi et al46 also reported a study of fractionated 131I-CC49 in 6 patients with CRC, all of whom received up to 4 infusions of RIT at 15 mCi/m2 per infusion. A total of 4 patients were able to receive all scheduled infusions. There was little immunogenicity because patients were also treated with deoxyspergualin, which limited the development of HAMAs in this study. Two phase I studies examined high-dose RIT followed by an autologous stem cell rescue using the anti-TAG-72 CC49 antibody. Tempero et al50 studied 14 patients who received high-dose 131I-CC49 (50-300 mCi/m2). Absorbed doses to tumor were calculated to be as high as 33 Gy. A total of 12 patients received autologous rescue. The same group performed a similar study with 90Y-CC49 in 12 patients at increasing doses from 0.3 to 0.5 mCi/kg.51 No objective responses were noted, but 2 patients had minor responses. Another antibody directed against TAG-72 is the chimeric IgG, cB72.3. Meredith et al52 reported the results of a phase I study of 131I-cB72.3 in patients with CRC. Doses ranged from 18 to 36 mCi/m2, with no significant dose-limiting toxicities (DLTs) identified. One-third of the patients showed evidence of minor responses. Epithelial cellular adhesion molecule (Ep-CAM) is highly expressed on gastrointestinal epithelium as well as CRC. Unlike CEA, it is not generally shed into the circulation, making Ep-CAM a promising RIT target. Antibodies binding to Ep-CAM tend to be 62 Cancer Control rapidly internalized into the cell, leading to excellent intratumoral retention of the antibody. Some of the earliest experience used the murine IgG 125I-CO 17-1A. A phase I study of 53 patients (25 with CRC) used 125I-CO 17-1A in a fractionated approach, with up to 17 cycles of therapy and with doses ranging from 3 to 25 mCi each cycle.53 Most of the patients also received whole-liver external beam radiotherapy in conjunction with the RIT. One PR and 11 mixed responses or SD were reported. No significant liver toxicity was seen with this combination therapy. The chimeric version of this antibody, 125I-17-1A, was evaluated in a phase I study, with 28 patients with CRC receiving 20 to 250 mCi.54 Ten patients who were reported to have SD from the RIT. No significant DLTs were reported in either study of RIT with the 17-1A antibody. NR-LU-10 is a murine IgG against Ep-CAM and has been evaluated in the phase I setting of 15 patients (10 with CRC).45 Labeled with 186Re, the antibody was not associated with objective responses, and all patients developed HAMAs. The MTD was found to be 90 mCi/m2. The chimeric version of this antibody, 186Re-NR-LU-13, was evaluated in a small phase I study.55 Patients were treated with 25 to 60 mCi/ m2. Two of the 9 patients had SD. The majority of patients demonstrated evidence of immunogenicity despite the chimeric nature of the antibody. A33 is another antigen highly expressed by colonic epithelium and CRC and is also not shed into the circulation. Like Ep-CAM, an antibody binding to A33 is internalized. Two phase I/II studies have been reported using the murine IgG, A33.56,57 Welt et al56 reported their experience with 131I-A33 in 23 patients with CRC in which 3 patients exhibited a mixed response to therapy, with a reported MTD of 75 mCi/ m2. The same group also performed a similar trial in 21 patients with CRC using 125I-A33.57 All patients were chemorefractory and received from 50 to 350 mCi/m2. They reported a single mixed response and no DLTs. A humanized version of the antibody was reported as part of a phase I study of 15 patients with CRC in which the MTD was reported to be 40 mCi/ m2.58 Four patients exhibited immunogenicity to the humanized antibody, and 4 patients demonstrated SD in response to RIT. In summary, there is a rich clinical experience of early phase clinical trials reported for RIT in patients with CRC. Several promising targets have been identified, including CEA, TAG-72, Ep-CAM, and A33. Overall, the results have been somewhat disappointing, with few objective responses. However, in the setting of minimal residual disease, some studies have demonstrated favorable progression-free survival (PFS) and OS compared with historic outcomes. Breast Cancer Breast cancer (BC) is the leading malignancy in women in the United States, with an estimated 226,870 new cases diagnosed in 2012, along with 39,510 deaths January 2013, Vol. 20, No. 1 from the disease.15,16 BC is also one of the more radiosensitive solid tumors, with external beam radiation capable of eliminating microscopic residual disease following lumpectomy.59,60 Several promising antigenic targets have been identified for RIT in BC, including CEA. T84.66, described above for its use in CRC, has also been studied in patients with BC. A phase I trial of 90Y-diethylenetriaminepentaacetate (DTPA)-cT84.66 in 7 patients with BC was reported by Wong et al.61 RIT was administered at 15 or 22.5 mCi/m2. No DLTs were reported, and all patients successfully engrafted following an autologous stem cell infusion. One PR and 2 cases of SD were described. MUC-1, a mucin epitope, is commonly expressed on the surface of BC cells. Several reports reveal efficient radioimmunodetection of BC using anti-MUC-1 monoclonal antibodies.62-65 Schrier et al66 reported on a phase I trial of high-dose murine 90Y-DTPA-BrE-3 and autologous stem cell rescue in 9 women with BC. Single RIT doses of 15 or 20 mCi/m2 were given, with no DLTs. One-half of the patients with measurable disease exhibited objective PRs to therapy.66 However, most patients developed HAMAs, limiting the ability to consider repeat dosing. A humanized version of the antibody has also been evaluated for use with stem cell support.67 Two patients exhibited objective PRs; each patient had a mixed response and SD. L6 is another antigen highly expressed on the surface of the majority of BC cells as well as some lung, prostate, and ovarian cancers and in the vascular endothelium.68 Investigators have studied a chimeric anti-L6 monoclonal antibody (131I-chL6) in patients with BC. Richman et al69 reported the results of a phase I study of fractionated 131I-chL6 RIT in the setting of high-dose therapy followed by autologous stem cell rescue. Three patients were treated with up to 3 cycles of RIT. One patient treated with cyclosporine did not develop HAMAs but the others did.69 The authors concluded that fractionation may allow for total dose escalation with less normal tissue toxicity and that cyclosporine may have a role in reducing the immunogenicity of RIT.69 The same group later reported the results of repeat dosing of 131I-chL6, up to 4 monthly cycles, without stem cell support in 10 patients with BC.70 Objective clinical responses were seen in one-half of those treated.70 The anti-TAG-72 monoclonal antibody CC49 has also been evaluated in BC, labeled with either lutetium-177 (177Lu) or 131I.49,71,72 Pretreatment with interferon alfa led to a nearly 50% increase in expression of TAG-72 on immunohistochemistry, which corresponded to a significantly increased uptake of 131I-CC49 in tumors.71,72 Patients exhibited 1 PR and 2 minor responses to therapy in a total of 15 participants.71,72 In summary, several active targets have been identified in BC for RIT, including CEA, TAG-72, MUC1, and L6. Modest responses have been seen, with greater responses in the setting of high-dose RIT followed by autologous stem cell rescue. Interferon alfa January 2013, Vol. 20, No. 1 may have the ability to upregulate expression of key RIT targets in patients with BC. Murine antibodies result in a high expression of HAMAs, limiting repeat dosing strategies. Prostate Cancer Prostate cancer (PC) is the most common noncutaneous malignancy in men in the United States, with an estimated 241,740 new cases and 28,170 deaths from the disease in 2012.15,16 It has been nearly 30 years since the first successful antibody targeting of PC.73 Perhaps the earliest clinical use of therapeutic RIT was reported by Meredith et al,74 who targeted TAG-72 with 131I-CC49 in 15 patients with androgen-independent PC. The antibody localized well to known areas of metastatic disease with no significant toxicity. However, there were no patients with a biochemical response, and all patients developed HAMAs. Of the patients with painful skeletal lesions, 60% described an improvement in their reported pain.74 A follow-up study by the same group used interferon alfa to increase tumor localization of 131I-CC49.75 They found an absorbed dose in excess of 25 Gy in the majority of visualized tumors. Two patients exhibited minor responses, and pain relief from skeletal metastases was common in this study. No major toxicities were reported. The L6 antigen, described above as a BC target, has also been evaluated for PC.76 O’Donnell et al77 examined 90Y-DOTA-chL6 in mice bearing PC xenografts and described a 100% response rate at an MTD of 150 mCi. Myelosuppression was seen but was fully reversible, and improved OS was seen in mice receiving the highest doses. The same group reported the results of a murine xenograft model, combining 90Y-DOTAchL6 and taxane chemotherapy. This resulted in a 67% cure rate for mice receiving both RIT and docetaxel, a 20% cure rate with RIT plus paclitaxel, and there was no cure rate in RIT alone, chemotherapy alone, or in the control groups.78 MUC-1 has also been shown to be upregulated in androgen-independent PC cells, making it a good target for RIT.79 A murine monoclonal antibody, m170, was initially examined in 17 patients with metastatic, androgen-independent PC in a phase I, dose-escalation trial labeled with 90Y.80 No DLTs were reached, and toxicity was limited to reversible myelosuppression. A majority of patients with pain at study entry reported a significant reduction in pain following therapy. The same group performed a phase I study of 90Y-2IT-BAD-m170 combined with low-dose paclitaxel in patients with PC.81 Two patients receiving combined modality therapy developed grade 4 neutropenia as opposed to none in the group receiving only RIT. Only 1 patient exhibited evidence of immunogenicity due to concurrent cyclosporine use. Prostate-specific membrane antigen (PSMA) is another rational PC target for RIT. PSMA is a hormone-independent, transmembrane glycoprotein that is minimally shed into the circulation and rarely exCancer Control 63 pressed outside the prostate.82 Once bound, PSMA becomes internalized into the PC cell, destined for endosomal recycling. CYT-356 (ProstaScint; Cytogen Corp, Princeton, NJ) is an 111In-labeled monoclonal antibody against the 7E11-C5.3 epitope of PSMA and is commercially used for imaging of metastatic PC foci. Deb et al83 reported the results of a phase I trial of escalating doses of 90Y-CYT-356 in 12 patients with metastatic PC. The MTD was 9 mCi/m2. No objective responses were reported, but higher doses seemed to be associated with longer PFS. No immunogenicity was seen in any patient at 4 weeks. J591, an IgG monoclonal antibody against the extracellular domain of PSMA, has also been evaluated in patients with PC.84 Labeled with the alpha-emitter bismuth-213 (213Bi), the antibody 213Bi-J591 was first described in a PC cell line and in athymic mice bearing PC xenografts, which is where it showed an ability to stop growth of PC spheroids in vitro and significantly reduce prostate-specific antigen (PSA) in vivo.85 Bander et al86 reported on a phase I trial of 177LuJ591 in 35 patients with androgen-independent metastatic PC. The single-dose MTD was determined to be 70 mCi/m2 and the repeat MTD was 30 mCi/m2 for up to 3 doses. There was no evidence of immunogenicity. A majority of patients exhibited a reduction or stabilization of PSA levels in response to therapy. Milowsky et al87 performed a similar phase I study using 90Y-J591 in 29 patients with metastatic PC. The MTD was reported to be 17.5 mCi/m2. Six patients exhibited stabilization of PSA, and 2 had significant drops in the tumor marker. The same group dosimetrically compared 177Lu-J591 with 90Y-J591 and reported that the absorbed dose to the bone marrow was approximately 3 times higher with 90Y, which was largely a function of the higher mean path length of the emitted beta particle.88 Ongoing phase II trials of 177Lu-J591 are currently open for accrual for patients with androgen-independent PC (NCT00859781, NCT00195039). In summary, a number of rational RIT targets have been described for PC, including TAG-72, L6, MUC-1, and PSMA. By contrast to most solid tumor types, patients with PC have exhibited some reasonable responses to RIT, particularly in the combined modality setting when delivered with taxane chemotherapy. Patients with PC who also have skeletal metastases experienced significant pain relief, even with RIT alone. The most promising agent currently in active clinical trials is 177Lu-J591, which targets PSMA. Ovarian Cancer Approximately 22,280 cases of ovarian cancer (OC) were diagnosed in the United States in 2012, with an estimated 15,500 deaths caused by the disease.15,16 Approximately 24 RIT constructs have been evaluated in preclinical and/or clinical studies. Intraperitoneal administration of RIT for advanced OC was first described more than 25 years ago.89 Human milk fat 64 Cancer Control globule (HMFG) 1 is a murine monoclonal antibody directed against MUC-1. A phase I/II clinical trial of intraperitoneal 90Y-HMFG1 suggested an extended PFS following CR to surgery and chemotherapy with RIT.90 The follow-up randomized controlled trial of intraperitoneal 90Y-HMFG1 showed no clinical benefit in adding an RIT agent compared with standard care following a complete clinical remission after chemotherapy and surgery.91 However, the study did show a decrease in intraperitoneal relapse rates.92 Placental-like alkaline phosphatase (PLAP) is a surface membrane enzyme expressed in the majority of ovarian tumors.93,94 Hu2PLAP is a human IgG monoclonal antibody directed against PLAP and has been used clinically for the radioimmunodetection of ovarian tumors, labeled with 111In and 123I. Both labeled agents were shown to localize to PLAP-positive ovarian tumors with no significant toxicity, and 2 of the 30 patients in the study exhibited immunogenicity.95 No therapeutic studies using Hu2PLAP have been reported to date. Trastuzumab is a humanized IgG monoclonal antibody directed against the extracellular domain of the oncoprotein human epidermal growth factor receptor 2 (HER-2)/neu, commonly overexpressed in breast, ovarian, and gastrointestinal tumors.96 This antibody has been labeled with several radionuclides for preclinical and clinical studies, including 90Y,97 177Lu,98 188Re,99 astatine-211 (211At),100,101 lead-212 (212Pb),102 actinium-225 (225Ac),103 and thorium-227 (227Th).104 There is an ongoing phase I study of intraperitoneal 212Pb-trastuzumab for patients with advanced OC with positive pelvic washings or peritoneal studding.105 Pertuzumab is a human monoclonal antibody directed against the HER-2 dimerization domain. Labeled with 177Lu, this agent has been evaluated in a murine xenograft model. Mice treated with 177Lupertuzumab exhibited a delayed tumor progression without evidence of significant toxicity.106 As with previously described solid tumors, TAG72 is frequently expressed on the surface of ovarian tumors. CC49, labeled with 90Y or 177Lu, has been evaluated in a number of OC clinical studies. Meredith et al107 reported the results of a phase I study in 12 patients with advanced OC, intraperitoneally delivering 177Lu-CC49. No MTD was reached up to 30 mCi/m2, and RIT was well tolerated, with only mild myelosuppression. Only 1 of 8 patients with gross disease showed an objective response, but 3 of the 4 patients with occult disease remained without evidence of progression after 18 months. The same group reported on a phase I/II study of intraperitoneal 177Lu-CC49 in 27 chemotherapy-refractory patients.108 As with the prior study, only 1 patient with gross disease responded, but 80% of those with occult disease remained disease-free for up to 3 years; the MTD was determined to be 45 mCi/m2. A phase I study of 90Y-CC49 was published by Alvarez et al109 in which 20 patients with OC and intra-abdominal January 2013, Vol. 20, No. 1 disease were treated with immunotherapy, paclitaxel, and escalated doses of 90Y-CC49. The MTD in this combined modality setting was 24.2 mCi/m2. Patients with nonmeasurable disease had durable responses, while 2 patients with measurable disease exhibited PRs to therapy. OC125 is a murine F(abʹ)2 monoclonal antibody fragment directed against CA-125, an OC tumor marker. Three clinical studies have been published using this antibody for intraperitoneal administration.110-112 In the first study, 90Y-OC125 was infused into 5 participants going for a second-look surgery.110 Intraoperative scintigraphy was performed to localize tumor foci for additional resection. In addition, the investigators performed normal organ dosimetric measurements that showed most of the infused dose remaining within the intraperitoneal space and approximately a 6:1 concentration of tumor to normal tissue. Mahé et al111 reported the results of a phase II trial of 131I-OC125 in patients with OC and minimal residual disease following surgery and chemotherapy. Participants received 120 mCi of RIT given intraperitoneally approximately 1 week following surgery. Three patients exhibited SD, while 3 progressed; all 6 patients demonstrated HAMAs following RIT, and the primary adverse events were hematologic. A phase I study by Muto et al112 examined escalating intraperitoneal doses of 131I-OC125 in women with refractory OC, with doses ranging from 18 to 144 mCi in a single dose. The MTD was reported to be 100 mCi, with unacceptable hematologic and gastrointestinal toxicity above this dose. The authors concluded that intraperitoneal RIT with 131I-OC125 was safe and feasible in this patient population. MOv18 is a murine or chimeric monoclonal antibody directed against a folate-binding protein present on the surface of nearly all ovarian carcinomas.113,114 Although the antibodies specifically target the folatebinding protein, significant heterogeneity was found between patients and even between tumor foci within patients following RIT, perhaps owing to differences in folate-binding protein in the tumors.115 The same group examined differences between intravenous and intraperitoneal administration of the 131I-labeled antibody and found no targeting benefits to intraperitoneal delivery but possibly less hematologic toxicity.116 Another intriguing potential target for RIT in OC is the cell-surface sodium-dependent phosphate transport protein 2b, recognized by the murine IgG MX35.117,118 A Swedish group119 has performed extensive preclinical studies on intraperitoneal delivery of the alpha-emitter-labeled antibody, 211At-MX35 F(abʹ)2. Nude mice inoculated intraperitoneally with OC xenografts were treated with either the targeted agent 211At-MX35 F(abʹ) or the nonspecific 211At-rituximab 2 F(abʹ)2. The alpha-labeled MX35 was significantly more effective at tumor kill, with a relatively higher mean absorbed dose (> 22 Gy) than is typically seen with beta-emitter–labeled antibodies. In a murine dose-escalation study,120 absorbed doses of up to 400 January 2013, Vol. 20, No. 1 Gy were intraperitoneally given, with posttherapy tumor-free fractions up to 61% with 211At-MX35 F(abʹ)2. An experiment that treated mice with one infusion vs repeated weekly infusions showed a significant improvement in tumor-free status with repeat therapy.121 In the one published clinical trial of this agent, 9 women with recurrent OC who were in complete remission following salvage systemic therapy were enrolled into a phase I study of intraperitoneal 211AtMX35 F(abʹ)2.122 No toxicity was observed, and only 6% of the infused dose was measurable in the serum, so the authors concluded that intraperitoneal therapy with 211At-MX35 F(abʹ)2 was both feasible and safe for patients with recurrent OC. Several other potential targets for RIT in OC have been described, but with little or no clinical experience.123-131 RIT for OC appears to be a potentially promising option, particularly in patients who have been optimally debulked following surgery and chemotherapy but who still are at high risk for microscopic intraperitoneal disease. Alpha-emitting radionuclides hold particular promise in nonbulky disease, given the higher linear energy transfer and shorter path length compared with beta particles. Therefore, the accrual of ongoing clinical trials of these novel agents should be encouraged. Pancreatic Cancer In general, pancreatic cancer (PanC) carries a poor prognosis. In 2012, approximately 43,920 new cases were diagnosed and 37,390 deaths occurred due to this disease.15,16 Particularly for unresectable cases, the median survival is shorter than 1 year, with few long-term survivors. The vast majority of PanC cases are mucin-producing adenocarcinomas, making MUC1 an attractive target for RIT.132 PAM4 is a murine monoclonal antibody directed against MUC-1, and early preclinical work demonstrated efficient targeting of PanC xenografts in athymic mice.133 Initial human studies of patients going for surgical resection used immunoscintigraphy to demonstrate the targeting of the 131I-radiolabeled PAM4 to PanC tumor cells.134 Both 131I-PAM4 and 90Y-PAM4 showed significant anti-PanC tumor effects in animal models, particularly when given concurrently with gemcitabine as a radiosensitizer.135-137 The first human therapeutic trial of the humanized version of the antibody (hPAM4) treated 20 patients with escalating single doses of 90Y-hPAM4 (15-25 mCi/m2).138 Objective responses were seen in 3 patients, and PFS was seen up to 5.6 months following treatment. However, most patients progressed within 1 month following RIT. The MTD was determined to be 20 mCi/m2 for a single infusion. In a phase I/II follow-up study of 100 patients, investigators examined the role of fractionated RIT concurrent with escalating doses of gemcitabine for radiosensitization.139 They found that the administration of multiple cycles of fractionated RIT was both Cancer Control 65 feasible and safe in patients with advanced PanC. Escalated doses of gemcitabine did not appear to improve responses. SD or objective responses were seen in 58% of the treated patients. Nearly one-half of patients treated with 1 or more cycles of RIT had an OS of longer than 1 year. A randomized trial of 90Y-hPAM4 with or without gemcitabine is currently in development to determine the role of the addition of the radiosensitizing agent.140 Hepatocellular Carcinoma Primary liver cancer is diagnosed in more than 500,000 people worldwide each year, including 25,000 in the United States.15,16 More than 90% of these are hepatocellular carcinomas (HCCs).141 Few patients are diagnosed at an early, resectable stage, making long-term survival for most patients poor, with a median survival shorter than 1 year.142 Early attempts at RIT for unresectable HCC using 131I–anti-alpha-fetoprotein (AFP) and 131I–anti-ferritin have yielded mixed results.2,143,144 131I–Hepama-1 was the first RIT agent developed to bind to a HCC membrane antigen, and early preclinical studies of human HCC xenografts in nude mice demonstrated that injections of the antibody led to objective responses and improved survival compared with controls.145 A phase I dose-escalation trial146 of the antibody in patients with unresectable HCC examined doses from 20 to 100 mCi. The treatments were well tolerated by all patients, and the 1-year OS rate was reported to be 31% (60% for patients without metastases). Three-fourths of patients with elevated AFP levels exhibited a 50% or greater reduction in the tumor marker. The HCC-associated membrane antigen HAb18G/ CD147 has also been identified as a potential RIT target, using the monoclonal antibody F(abʹ)2 fragment 131I-metuximab as a hepatic artery infusion. A phase I/II study determined the MTD to be 0.75 mCi/kg body weight per cycle and, of the 73 patients receiving 2 cycles of RIT, 20 had objective responses and 43 exhibited SD in response to therapy.147 Median OS was 19 months. In a separate report, the group demonstrated highly specific tumor-to-normal-tissue absorbed doses.148 Central Nervous System The blood–brain barrier hinders the transport of most large molecules such as proteins from entering the central nervous system (CNS). Although tumor-initiated angiogenesis may result in more permeable microvasculature, this is typically not sufficient to allow for significant delivery of antibodies and antibody fragments to the CNS.149 The addition of external beam radiotherapy can further disrupt the blood–brain barrier by increasing the vascular permeability.150-152 Most attempts at RIT for CNS malignancies have focused on direct intratumoral or intracavitary administration. Perhaps the target most investigated for CNS tumors is tenascin, a glycoprotein concentrated within 66 Cancer Control the extracellular matrix of malignant gliomas.153 Riva et al154 first reported on antitenascin RIT in a study of 10 patients with recurrent glioblastoma (GBM) who received intratumoral administration of 131I-BC2, a murine monoclonal antibody directed against tenascin. The mean specific activity per injection was approximately 15 mCi, and most patients received multiple injections. Cumulative tumor doses ranged from 70 to 410 Gy. The injections were well tolerated without systemic effects. Responses included 1 patient with CR, 2 with PRs, and 3 with SD, and all responders were relapse-free for at least 11 months.154 In a separate report by the same group of 24 patients with relapsed gliomas, antitenascin RIT was given in doses from 15 to 57 mCi, with up to 4 repeated doses.155 No significant toxicities were observed, and the median survival was 16 months. Of 17 evaluable patients, 3 reported a CR, 3 had a PR, and 5 had SD. Riva et al156 also examined the role of 131I antitenascin RIT in patients with newly diagnosed malignant gliomas following surgical resection and chemoradiotherapy in a study of 50 patients: 26 had recurrent disease and 24 had been newly diagnosed. Patients received up to 6 repeated infusions, with doses up to 300 Gy per infusion. The median OS was 20 months for all patients (18 for relapsed disease and 23 for the newly diagnosed), with a 40% overall response rate. The group later performed a phase I study of 90Y-BC-4, another antitenascin murine antibody, in 20 patients with recurrent high-grade gliomas.157 Doses ranged from 5 to 30 mCi with an MTD of 25 mCi. The mean tumor dose was 3200 cGy/mCi, and no systemic toxicity was seen. The use of 90Y demonstrated improved responses compared with 131I for bulky residual disease and with fewer radioprotection concerns due to the lack of gamma emissions.158 Another antitenascin radiolabeled monoclonal antibody, 131I-81C6, was evaluated in a phase 1 study in 34 patients with previously irradiated glioma who also had surgically created resection cavities.159 Doses ranged from 20 to 120 mCi, with the MTD determined to be 100 mCi. Neurologic toxicity was dose limiting, with significant hematologic toxicity seen only at the 120 mCi level, and median survival for all treated patients was 60 weeks. The same group reported the results of a phase I study in patients who were newly diagnosed with malignant glioma following surgery and had not received additional adjuvant therapy.160 Doses ranged from 20 to 180 mCi with, an MTD of 120 mCi. DLT was primarily delayed neurotoxicity. One patient required surgery for symptomatic radiation necrosis. Median survival for all patients was 79 weeks. In a follow-up phase II trial in 33 patients with newly diagnosed high-grade glioma receiving 120 mCi 131I-81C6 followed by adjuvant chemoradiation, the median OS was 86.7 weeks for all patients and 79.4 weeks for those with GBM.161 A dosimetric analysis from this trial suggested that the tumor cavity absorbed a dose of 44 Gy provided optimal clinical January 2013, Vol. 20, No. 1 outcomes.162 A phase II study in 43 patients with recurrent disease receiving 100 mCi 131I-81C6 showed median survivals of 99 and 64 weeks for anaplastic and GBM patients, respectively.163 A phase I study of a chimeric construct of 131I-81C6 reported an MTD of 80 mCi and suggested greater hematologic toxicity than was seen with the murine antibody.164 The epidermal growth factor receptor (EGFR), a transmembrane glycoprotein, is expressed in a variety of tissues and its expression in gliomas increases in conjunction with grade, and it is present in a majority of cases of GBM.165 Early evidence of the efficacy of anti-EGFR RIT was reported in a pilot study by Brady et al.166 A total of 15 patients with recurrent malignant glioma were treated with 125I-labeled anti–EGFR-425, given intra-arterially via either the carotid or vertebral arteries. They reported 1 CR, 2 PRs, and 5 patients with SD in response to treatment. The same group performed a phase II trial of 125I-425 in 25 patients with multiple infusions and cumulative doses, ranging from 40 to 224 mCi, following surgical resection and adjuvant external beam radiotherapy.167 Median survival was reported to be 15.6 months, with more than 60% of patients alive at 1 year. Recently, Li et al168 published the results of a phase II trial of 125I-425, with or without temozolomide, in 192 patients with GBM following surgical resection. Median survival following RIT alone was 14.5 months vs 20.2 months for the temozolomide arm, representing a 38% reduction in the risk of death with the addition of concurrent chemotherapy. Leptomeningeal disease (LMD) represents a unique form of CNS malignancy, and intraventricular administration of RIT has been investigated in several studies. Kramer et al169 reported on the use of 131I3F8, a murine monoclonal antibody directed against disialoganglioside (GD2). Five patients with LMD expressing GD2 received intraventricular administration of 1 to 2 mCi of 131I-3F8. Single-photon emission computed tomography imaging predicted doses of 15 to 56 cGy/mCi to the cerebral spinal fluid (CSF) compared with less than 2 cGy/mCi to extracranial tissues. In a formal phase I study of intraventricular 131I-3F8, 15 patients with GD2+ LMD received from 10 to 20 mCi after acceptable CSF flow was demonstrated with a dosimetric dose.170 The total dose to the CSF ranged from 1 to 13 Gy. DLT was seen at the higher dose level, including chemical meningitis, and, of the 13 assessable patients, 3 exhibited a CR and 2 remained in remission for at least 3.5 years. Antitumor Necrosis Therapy Although most RIT approaches have endeavored to target specific tumor membrane antigens, one alternative is to target regions of tumors undergoing necrosis, either secondary to therapy or to degeneration. These dead and dying cells exhibit increased permeability of the cell membrane, and previous studies have shown increased uptake of circulating proteins.171,172 Epstein January 2013, Vol. 20, No. 1 et al173 reported on the development of monoclonal antibodies directed against the DNA-histone H1 complex seen in dying cells. Tumor-bearing nude mice were injected with 131I–TNT-1, an F(abʹ)2 IgG fragment, and necrotic tumor-to-blood ratios were greater than 100:1, showing highly specific accumulation in areas of tumor necrosis. Since that early report, radiolabeled TNT-1 has been investigated in a number of malignancies, including cervical, colon, brain, and lung cancers as well as hepatic metastases.174-179 The antibody was approved by the Chinese State Food and Drug Administration in 2003 for the treatment of advanced lung cancer, and it appears to have little immunogenicity in clinical practice.180 Conclusions Significant advancements have been made in the development of RIT during the last 60 years. Progress in chimerization and humanization of monoclonal antibodies, the use of antibody fragments, pretargeting methods, improved dosimetric models, and novel radionuclides — including alpha-emitters — have opened the field beyond simply B-cell non-Hodgkin lymphomas. Several new RIT agents are under active clinical investigation for many solid tumor types. Many of these are entering phase II and III clinical trials, and physicians and their patients with cancer should be encouraged to consider participating in these important endeavors.181 References 1. Pressman D, Korngold L. The in vivo localization of anti-Wagnerosteogenic-sarcoma antibodies. Cancer. 1953;6(3):619-623. 2. Order SE, Stillwagon GB, Klein JL, et al. Iodine 131 antiferritin, a new treatment modality in hepatoma: a Radiation Therapy Oncology Group study. J Clin Oncol. 1985;3(12):1573-1582. 3. Goldenberg DM, DeLand F, Kim E, et al. Use of radiolabeled antibodies to carcinoembryonic antigen for the detection and localization of diverse cancers by external photoscanning. N Engl J Med. 1978;298(25):1384-1386. 4. Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256(5517):495-497. 5. DeNardo SJ, Erickson KL, Benjamini E. Use of I-131 antibodies for radiation therapy. Clin Nucl Med. 1980; 5:S4-S5. Abstract. 6. DeNardo SJ, Erickson KL, Benjamini E, et al. Radioimmunotherapy for melanoma. Clin Cancer Res. 1981;29:434A. Abstract. 7. Carrasquillo JA, Krohn KA, Beaumier P, et al. Diagnosis of and therapy for solid tumors with radiolabeled antibodies and immune fragments. Cancer Treat Rep. 1984;68(1):317-328. 8. Goldenberg DM. Targeted therapy of cancer with radiolabeled antibodies. J Nucl Med. 2002;43(5):693-713. 9. U.S. Food and Drug Administration, U.S. Department of Health & Human Services. Rituximab product approval letter, November 26, 1997. http:// www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm107740.pdf. Accessed November 12, 2012. 10. U.S. Food and Drug Administration, U.S. Department of Health & Human Services. Ibritumomab tiuxetan product approval letter, February 19, 2002. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/ HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm113489.pdf. Accessed November 12, 2012. 11. U.S. Food and Drug Administration, U.S. Department of Health & Human Services. Tositumomab and iodine I 131 tositumomab product approval information, June 27, 2003. http://www.fda.gov/Drugs/Development ApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/ TherapeuticBiologicApplications/ucm080503.htm. Accessed November 12, 2012. 12. Tomblyn M, Elstrom R, Himelstein AL, et al. Novel combination of anti-CD22 radioimmunotherapy and anti-CD20 immunotherapy targeting two different antigens in non-Hodgkin lymphoma (NHL): initial clinical experience. J Nucl Med. 2012;53(suppl 1). Abstract 500. Cancer Control 67 13. Tomblyn M. Radioimmunotherapy for B-cell non-Hodgkin lymphomas. Cancer Control. 2012;19(3):196-203. 14. Goldenberg DM. Targeted therapy of cancer with radiolabeled antibodies. J Nucl Med. 2002;43(5):693-713. 15. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012. http://www.cancer.org/acs/groups/ content/@epidemiologysurveilance/documents/document/acspc-031941. pdf. Accessed November 12, 2012. 16. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10-29. 17. Blumenthal RD, Sharkey RM, Kashi R, et al. Comparison of therapeutic efficacy and host toxicity of two different 131I-labelled antibodies and their fragments in the GW-39 colonic cancer xenograft model. Int J Cancer. 1989;44(2):292-300. 18. Blumenthal RD, Sharkey RM, Haywood L, et al. Targeted therapy of athymic mice bearing GW-39 human colonic cancer micrometastases with 131I-labeled monoclonal antibodies. Cancer Res. 1992;52(21):6036-6044. 19. Sharkey RM, Blumenthal RD, Behr TM, et al. Selection of radioimmunoconjugates for the therapy of well-established or micrometastatic colon carcinoma. Int J Cancer. 1997;72(3):477-485. 20. Behr TM, Memtsoudis S, Sharkey RM, et al. Experimental studies on the role of antibody fragments in cancer radio-immunotherapy: influence of radiation dose and dose rate on toxicity and anti-tumor efficacy. Int J Cancer. 1998;77(5):787-795. 21. Behr TM, Sharkey RM, Juweid MI, et al. Factors influencing the pharmacokinetics, dosimetry, and diagnostic accuracy of radioimmunodetection and radioimmunotherapy of carcinoembryonic antigen-expressing tumors. Cancer Res. 1996;56(8):1805-1816. 22. Sgouros G. Radioimmunotherapy of micrometastases: sidestepping the solid-tumor hurdle. J Nucl Med. 1995;36(10):1910-1912. 23. Behr TM, Salib AL, Liersch T, et al. Radioimmunotherapy of small volume disease of colorectal cancer metastatic to the liver: preclinical evaluation in comparison to standard chemotherapy and initial results of a phase I clinical study. Clin Cancer Res. 1999;5(10 suppl):3232s-3242s. 24. Gold P, Freedman SO. Demonstration of tumor-specific antigens in human colonic carcinomata by immunological tolerance and absorption techniques. J Exp Med. 1965;121:439-462. 25. Lane DM, Eagle KF, Begent RH, et al. Radioimmunotherapy of metastatic colorectal tumours with iodine-131-labelled antibody to carcinoembryonic antigen: phase I/II study with comparative biodistribution of intact and F(abʹ)2 antibodies. Br J Cancer. 1994;70(3):521-525. 26. Behr TM, Sharkey RM, Juweid ME, et al. Phase I/II clinical radioimmunotherapy with an iodine-131-labeled anti-carcinoembryonic antigen murine monoclonal antibody IgG. J Nucl Med. 1997;38(6):858-870. 27. Juweid ME, Sharkey RM, Behr T, et al. Radioimmunotherapy of patients with small-volume tumors using iodine-131-labeled anti-CEA monoclonal antibody NP-4 F(abʹ)2. J Nucl Med. 1996;37(9):1504-1510. 28. Juweid M, Sharkey RM, Swayne LC, et al. Pharmacokinetics, dosimetry and toxicity of rhenium-188-labeled anti-carcinoembryonic antigen monoclonal antibody, MN-14, in gastrointestinal cancer. J Nucl Med. 1998;39(1):34-42. 29. Hajjar G, Sharkey RM, Burton J, et al. Phase I radioimmunotherapy trial with iodine-131-labeled humanized MN-14 anti-carcinoembryonic antigen monoclonal antibody in patients with metastatic gastrointestinal and colorectal cancer. Clin Colorectal Cancer. 2002;2(1):31-42. 30. Behr TM, Liersch T, Greiner-Bechert L, et al. Radioimmunotherapy of small-volume disease of metastatic colorectal cancer. Cancer. 2002;94(4 suppl):1373-1381. 31. Liersch T, Meller J, Bittrich M, et al. Update of carcinoembryonic antigen radioimmunotherapy with (131)I-labetuzumab after salvage resection of colorectal liver metastases: comparison of outcome to a contemporaneous control group. Ann Surg Oncol. 2007;14(9):2577-2590. 32. Liersch T, Meller J, Bittrich M, et al. Update of carcinoembryonic antigen radioimmunotherapy with (131)I-labetuzumab after salvage resection of colorectal liver metastases: comparison of outcome to a contemporaneous control group. Ann Surg Oncol. 2007;14(9):2577-2590. 33. Liersch T, Meller J, Sahlmann C, et al. Repeated anti-CEA-radioimmunotherapy (RAIT) with 131iodine-labetuzumab (phase II study) versus single dose RAIT after salvage resection of colorectal liver metastases (CRC-LM). J Clin Oncol. 2008;26(20 suppl):4080. Abstract. 34. Beatty JD, Duda RB, Williams LE, et al. Preoperative imaging of colorectal carcinoma with 111In-labeled anticarcinoembryonic antigen monoclonal antibody. Cancer Res. 1986;46(12 Pt 1):6494-6502. 35. Wong JYC, Chu DZ, Yamauchi DM, et al. A phase I radioimmunotherapy trial evaluating 90yttrium-labeled anti-carcinoembryonic antigen (CEA) chimeric T84.66 in patients with metastatic CEA-producing malignancies. Clin Cancer Res. 2000;6(10):3855-3863. 36. Wong JY, Chu DZ, Williams LE, et al. A phase I trial of (90)Y-DOTAanti-CEA chimeric T84.66 (cT84.66) radioimmunotherapy in patients with metastatic CEA-producing malignancies. Cancer Biother Radiopharm. 2006; 21(2):88-100. 37. Wong JY, Shibata S, Williams LE, et al. A phase I trial of 90Y-anticarcinoembryonic antigen chimeric T84.66 radioimmunotherapy with 5-fluorouracil in patients with metastatic colorectal cancer. Clin Cancer Res. 68 Cancer Control 2003;9(16 Pt 1):5842-5852. 38. Shibata S, Raubitschek A, Leong L, et al. A phase I study of a combination of yttrium-90-labeled anti-carcinoembryonic antigen (CEA) antibody and gemcitabine in patients with CEA-producing advanced malignancies. Clin Cancer Res. 2009;15(8):2935-2941. 39. Behr TM, Sharkey RM, Juweid ME, et al. Phase I/II clinical radioimmunotherapy with an iodine-131-labeled anti-carcinoembryonic antigen murine monoclonal antibody IgG. J Nucl Med. 1997;38(6):858-870. 40. Juweid ME, Sharkey RM, Behr T, et al. Radioimmunotherapy of patients with small-volume tumors using iodine-131-labeled anti-CEA monoclonal antibody NP-4 F(abʹ)2. J Nucl Med. 1996;37(9):1504-1510. 41. Ychou M, Pelegrin A, Faurous P, et al. Phase-I/II radio-immunotherapy study with Iodine-131-labeled anti-CEA monoclonal antibody F6 F(abʹ)2 in patients with non-resectable liver metastases from colorectal cancer. Int J Cancer. 1998;75(4):615-619. 42. Ychou M, Azria D, Menkarios C, et al. Adjuvant radioimmunotherapy trial with iodine-131-labeled anti-carcinoembryonic antigen monoclonal antibody F6 F(abʹ)2 after resection of liver metastases from colorectal cancer. Clin Cancer Res. 2008;14(11):3487-3493. 43. Gaya AM, Violet J, Dancey G, et al. A phase I/II trial of radioimmunotherapy with 131Iodine labelled A5B7 anti-CEA antibody (131I-A5B7) in combination with combretastatin-A4-phosphate (CA4P) in advanced gastrointestinal carcinomas. J Clin Oncol. 2008;26(20 suppl):14517. Abstract. 44. Yu B, Carrasquillo J, Milenic D, et al. Phase I trial of iodine 131labeled COL-1 in patients with gastrointestinal malignancies: influence of serum carcinoembryonic antigen and tumor bulk on pharmacokinetics. J Clin Oncol. 1996;14(6):1798-1809. 45. Breitz HB, Weiden PL, Vanderheyden JL, et al. Clinical experience with rhenium-186-labeled monoclonal antibodies for radioimmunotherapy: results of phase I trials. J Nucl Med. 1992;33(6):1099-1109. 46. Divgi CR, Scott AM, Dantis L, et al. Phase I radioimmunotherapy trial with iodine-131-CC49 in metastatic colon carcinoma. J Nucl Med. 1995;36 (4): 586-592. 47. Murray JL, Macey DJ, Kasi LP, et al. Phase II radioimmunotherapy trial with 131I-CC49 in colorectal cancer. Cancer. 1994;73(3 suppl):1057-1066. 48. Wheeler RH, Meredith RF, Saleh MN, et al. A phase II trial of IL-1 + radioimmunotherapy (RIT) in patients (pts) with metastatic colon cancer. J Clin Oncol. 1994;13:295. Abstract 959. 49. Mulligan T, Carrasquillo JA, Chung Y, et al. Phase I study of intravenous Lu-labeled CC49 murine monoclonal antibody in patients with advanced adenocarcinoma. Clin Cancer Res. 1995;1(12):1447-1454. 50. Tempero M, Leichner P, Dalrymple G, et al. High-dose therapy with iodine-131-labeled monoclonal antibody CC49 in patients with gastrointestinal cancers: a phase I trial. J Clin Oncol. 1997;15(4):1518-1528. 51. Tempero M, Leichner P, Baranowska-Kortylewicz J, et al. High-dose therapy with 90Yttrium-labeled monoclonal antibody CC49: a phase I trial. Clin Cancer Res. 2000;6(8):3095-3102. 52. Meredith RF, Khazaeli MB, Plott WE, et al. Phase I trial of iodine131-chimeric B72.3 (human IgG4) in metastatic colorectal cancer. J Nucl Med. 1992;33(1):23-29. 53. Markoe AM, Brady LW, Woo D, et al. Treatment of gastrointestinal cancer using monoclonal antibodies. Front Radiat Ther Oncol. 1990;24:214-227. 54. Meredith RF, Khazaeli MB, Plott WE, et al. Initial clinical evaluation of iodine-125-labeled chimeric 17-1A for metastatic colon cancer. J Nucl Med. 1995;36(12):2229-2233. 55. Weiden PL, Breitz HB, Seiler CA, et al. Rhenium-186-labeled chimeric antibody NR-LU-13: pharmacokinetics, biodistribution and immunogenicity relative to murine analog NR-LU-10. J Nucl Med. 1993;34(12):2111-2119. 56. Welt S, Divgi CR, Kemeny N, et al. Phase I/II study of iodine 131labeled monoclonal antibody A33 in patients with advanced colon cancer. J Clin Oncol. 1994;12(8):1561-1571. 57. Welt S, Scott AM, Divgi CR, et al. Phase I/II study of iodine 125labeled monoclonal antibody A33 in patients with advanced colon cancer. J Clin Oncol. 1996;14(6):1787-1797. 58. Chong G, Lee FT, Hopkins W, et al. Phase I trial of 131I-huA33 in patients with advanced colorectal carcinoma. Clin Cancer Res. 2005;11(13): 4818-4826. 59. Fisher B, Redmond C, Poisson R, et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med. 1989;320(13):822-828. 60. Sarrazin D, Lê MG, Arriagada R, et al. Ten-year results of a randomized trial comparing a conservative treatment to mastectomy in early breast cancer. Radiother Oncol. 1989;14(3):177-184. 61. Wong JY, Somlo G, Odom-Maryon T, et al. Initial clinical experience evaluating Yttrium-90-chimeric T84.66 anticarcinoembryonic antigen antibody and autologous hematopoietic stem cell support in patients with carcinoembryonic antigen-producing metastatic breast cancer. Clin Cancer Res. 1999;5(10 suppl):3224s-3231s. 62. Major PP, Dion AS, Williams CJ, et al. Breast tumor radioimmunodetection with a 111In-labeled monoclonal antibody (MA5) against a mucin-like antigen. Cancer Res. 1990;50(3 suppl):927s-931s. 63. Kramer EL, DeNardo SJ, Liebes L, et al. Radioimmunolocalization of metastatic breast carcinoma using indium-111-methyl benzyl DTPA BrE-3 January 2013, Vol. 20, No. 1 monoclonal antibody: phase I study. J Nucl Med. 1993;34(7):1067-1074. 64. Granowska M, Biassoni L, Carroll MJ, et al. Breast cancer 99mTc SM3 radioimmunoscintigraphy. Acta Oncol. 1996;35(3):319-321. 65. Baum RP, Brümmendorf TH. Radioimmunolocalization of primary and metastatic breast cancer. Q J Nucl Med. 1998;42(1):33-42. 66. Schrier DM, Stemmer SM, Johnson T, et al. High-dose 90Y Mx-diethylenetriaminepentaacetic acid (DTPA)-BrE-3 and autologous hematopoietic stem cell support (AHSCS) for the treatment of advanced breast cancer: a phase I trial. Cancer Res. 1995;55(23 suppl):5921s-5924s. 67. Cagnoni PJ, Ceriani RL, Cole WC, et al. Phase I study of high-dose radioimmunotherapy with 90-Y-hu-BrE-3 followed by autologous stem cell support (ASCS) in patients with metastatic breast cancer. Cancer Biother Radiopharm. 1998;13(4):328. Abstract 92. 68. Marken JS, Schieven GL, Hellström I, et al. Cloning and expression of the tumor-associated antigen L6. Proc Natl Acad Sci U S A. 1992;89(8):3503-3507. 69. Richman CM, DeNardo SJ, O’Grady LF, et al. Radioimmunotherapy for breast cancer using escalating fractionated doses of 131I-labeled chimeric L6 antibody with peripheral blood progenitor cell transfusions. Cancer Res. 1995;55(23 suppl):5916s-5920s. 70. Denardo SJ, O’Grady LF, Richman CM, et al. Radioimmunotherapy for advanced breast cancer using I-131-ChL6 antibody. Anticancer Res. 1997;17(3B):1745-1751. 71. Macey DJ, Grant EJ, Kasi L, et al. Effect of recombinant alpha-interferon on pharmacokinetics, biodistribution, toxicity, and efficacy of 131Ilabeled monoclonal antibody CC49 in breast cancer: a phase II trial. Clin Cancer Res. 1997;3(9):1547-1555. 72. Murray JL, Macey DJ, Grant EJ, et al. Enhanced TAG-72 expression and tumor uptake of radiolabeled monoclonal antibody CC49 in metastatic breast cancer patients following alpha-interferon treatment. Cancer Res. 1995;55(23 suppl):5925s-5928s. 73. Goldenberg DM, DeLand FH, Bennett SJ, et al. Radioimmunodetection of prostatic cancer. In vivo use of radioactive antibodies against prostatic acid phosphatase for diagnosis and detection of prostatic cancer by nuclear imaging. JAMA. 1983;250(5):630-635. 74. Meredith RF, Bueschen AJ, Khazaeli MB, et al, Treatment of metastatic prostate carcinoma with radiolabeled antibody CC49. J Nucl Med. 1994;35(6):1017-1022. 75. Meredith RF, Khazaeli MB, Macey DJ, et al. Phase II study of interferon-enhanced 131I-labeled high affinity CC49 monoclonal antibody therapy in patients with metastatic prostate cancer. Clin Cancer Res. 1999;5(10 suppl):3254s-3258s. 76. O’Donnell RT, DeNardo SJ, Shi XB, et al. L6 monoclonal antibody binds prostate cancer. Prostate. 1998;37(2):91-97. 77. O’Donnell RT, DeNardo SJ, DeNardo GL, et al. Efficacy and toxicity of radioimmunotherapy with (90)Y-DOTA-peptide-ChL6 for PC3-tumored mice. Prostate. 2000;44(3):187-192. 78. O’Donnell RT, DeNardo SJ, Miers LA, et al. Combined modality radioimmunotherapy for human prostate cancer xenografts with taxanes and 90yttrium-DOTA-peptide-ChL6. Prostate. 2002;50(1):27-37. 79. DeNardo SJ, Richman CM, Albrecht H, et al. Enhancement of the therapeutic index: from nonmyeloablative and myeloablative toward pretargeted radioimmunotherapy for metastatic prostate cancer. Clin Cancer Res. 2005;11(19 pt 2):7187s-7194s. 80. O’Donnell RT, DeNardo SJ, Yuan A, et al. Radioimmunotherapy with (111)In/(90)Y-2IT-BAD-m170 for metastatic prostate cancer. Clin Cancer Res. 2001;7(6):1561-1568. 81. Richman CM, Denardo SJ, O’Donnell RT, et al. High-dose radioimmunotherapy combined with fixed, low-dose paclitaxel in metastatic prostate and breast cancer by using a MUC-1 monoclonal antibody, m170, linked to indium-111/yttrium-90 via a cathepsin cleavable linker with cyclosporine to prevent human anti-mouse antibody. Clin Cancer Res. 2005;11(16):59205927. 82. Abdel-Nabi H, Wright GL, Gulfo JV, et al. Monoclonal antibodies and radioimmunoconjugates in the diagnosis and treatment of prostate cancer. Semin Urol. 1992;10(1):45-54. 83. Deb N, Goris M, Trisler K, et al. Treatment of hormone-refractory prostate cancer with 90Y-CYT-356 monoclonal antibody. Clin Cancer Res. 1996;2(8):1289-1297. 84. Chang SS, Reuter VE, Heston WD, et al. Five different anti-prostatespecific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated neovasculature. Cancer Res. 1999;59(13):3192-3198. 85. McDevitt MR, Barendswaard E, Ma D, et al. An alpha-particle emitting antibody ([213Bi]J591) for radioimmunotherapy of prostate cancer. Cancer Res. 2000;60(21):6095-6100. 86. Bander NH, Milowsky MI, Nanus DM, et al. Phase I trial of 177lutetium-labeled J591, a monoclonal antibody to prostate-specific membrane antigen, in patients with androgen-independent prostate cancer. J Clin Oncol. 2005;23(21):4591-4601. 87. Milowsky MI, Nanus DM, Kostakoglu L, et al. Phase I trial of yttrium-90-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for androgen-independent prostate cancer. J Clin Oncol. 2004;22(13):2522-2531. 88. Vallabhajosula S, Kuji I, Hamacher KA, et al. Pharmacokinetics and January 2013, Vol. 20, No. 1 biodistribution of 111In- and 177Lu-labeled J591 antibody specific for prostate-specific membrane antigen: prediction of 90Y-J591 radiation dosimetry based on 111In or 177Lu? J Nucl Med. 2005;46(4):634-641. 89. Epenetos AA, Munro AJ, Stewart S, et al. Antibody-guided irradiation of advanced ovarian cancer with intraperitoneally administered radiolabeled monoclonal antibodies. J Clin Oncol. 1987;5(12):1890-1899. 90. Hird V, Maraveyas A, Snook D, et al. Adjuvant therapy of ovarian cancer with radioactive monoclonal antibody. Br J Cancer. 1993;68(2):403-406. 91. Verheijen RH, Massuger LF, Benigno BB, et al. Phase III trial of intraperitoneal therapy with yttrium-90-labeled HMFG1 murine monoclonal antibody in patients with epithelial ovarian cancer after a surgically defined complete remission. J Clin Oncol. 2006;24(4):571-578. 92. Oei AL, Verheijen RH, Seiden MV, et al. Decreased intraperitoneal disease recurrence in epithelial ovarian cancer patients receiving intraperitoneal consolidation treatment with yttrium-90-labeled murine HMFG1 without improvement in overall survival. Int J Cancer. 2007;120(12):2710-2714. 93. Benham FJ, Povey MS, Harris H. Placental-like alkaline phosphatase in malignant and benign ovarian tumors. Clin Chim Acta. 1978;86(2):201215. 94. Sunderland CA, Davies JO, Stirrat GM. Immunohistology of normal and ovarian cancer tissue with a monoclonal antibody to placental alkaline phosphatase. Cancer Res. 1984;44(10):4496-4502. 95. Kosmas C, Kalofonos HP, Hird V, Epenetos AA. Monoclonal antibody targeting of ovarian carcinoma. Oncology. 1998;55(5):435-446. 96. Carter P, Presta L, Gorman CM, et al. Humanization of an antip185HER2 antibody for human cancer therapy. Proc Natl Acad Sci U S A. 1992;89(10):4285-4289. 97. Crow DM, Williams L, Colcher D, et al. Combined radioimmunotherapy and chemotherapy of breast tumors with Y-90-labeled anti-Her2 and antiCEA antibodies with taxol. Bioconjug Chem. 2005;16(5):1117-1125. 98. Rasaneh S, Rajabi H, Babaei MH, et al. 177Lu labeling of Herceptin and preclinical validation as a new radiopharmaceutical for radioimmunotherapy of breast cancer. Nucl Med Biol. 2010;37(8):949-955. 99. Chen KT, Lee TW, Lo JM. In vivo examination of (188)Re(I)-tricarbonyl-labeled trastuzumab to target HER2-overexpressing breast cancer. Nucl Med Biol. 2009;36(4):355-361. 100. Akabani G, Carlin S, Welsh P, et al. In vitro cytotoxicity of 211Atlabeled trastuzumab in human breast cancer cell lines: effect of specific activity and HER2 receptor heterogeneity on survival fraction. Nucl Med Biol. 2006;33(3):333-347. 101. Palm S, Bäck T, Claesson I, et al. Therapeutic efficacy of astatine211-labeled trastuzumab on radioresistant SKOV-3 tumors in nude mice. Int J Radiat Oncol Biol Phys. 2007;69(2):572-579. 102. Milenic DE, Garmestani K, Brady ED, et al. Alpha-particle radioimmunotherapy of disseminated peritoneal disease using a (212)Pb-labeled radioimmunoconjugate targeting HER2. Cancer Biother Radiopharm. 2005;20(5):557-568. 103. Borchardt PE, Yuan RR, Miederer M, et al. Targeted actinium-225 in vivo generators for therapy of ovarian cancer. Cancer Res. 2003;63(16):50845090. 104. Abbas N, Heyerdahl H, Bruland OS, et al. Experimental α-particle radioimmunotherapy of breast cancer using 227Th-labeled p-benzyl-DOTAtrastuzumab. EJNMMI Res. 2011;1(1):18. 105. Meredith RF. Safety study of ²¹²Pb-TCMC-trastuzumab radio immunotherapy. http://clinicaltrials.gov/ct2/show/NCT01384253. Accessed November 12, 2012. 106. Persson M, Gedda L, Lundqvist H, et al. [177Lu]pertuzumab: experimental therapy of HER-2-expressing xenografts. Cancer Res. 2007;67(1):326-331. 107. Meredith RF, Partridge EE, Alvarez RD, et al. Intraperitoneal radioimmunotherapy of ovarian cancer with lutetium-177-CC49. J Nucl Med. 1996;37(9):1491-1496. 108. Alvarez RD, Partridge EE, Khazaeli MB, et al. Intraperitoneal radioimmunotherapy of ovarian cancer with 177Lu-CC49: a phase I/II study. Gynecol Oncol. 1997;65(1):94-101. 109. Alvarez RD, Huh WK, Khazaeli MB, et al. A phase I study of combined modality (90)yttrium-CC49 intraperitoneal radioimmunotherapy for ovarian cancer. Clin Cancer Res. 2002;8(9):2806-2811. 110. Hnatowich DJ, Chinol M, Siebecker DA, et al. Patient biodistribution of intraperitoneally administered yttrium-90-labeled antibody. J Nucl Med. 1988;29(8):1428-1435. 111. Mahé MA, Fumoleau P, Fabbro M, et al. A phase II study of intraperitoneal radioimmunotherapy with iodine-131-labeled monoclonal antibody OC-125 in patients with residual ovarian carcinoma. Clin Cancer Res. 1999;5(10 suppl):3249s-3253s. 112. Muto MG, Finkler NJ, Kassis AI, et al. Intraperitoneal radioimmunotherapy of refractory ovarian carcinoma utilizing iodine-131-labeled monoclonal antibody OC125. Gynecol Oncol. 1992;45(3):265-272. 113. Campbell IG, Jones TA, Foulkes WD, et al. Folate-binding protein is a marker for ovarian cancer. Cancer Res. 1991;51(19):5329-5338. 114. Molthoff CF, Buist MR, Kenemans P, et al. Experimental and clinical analysis of the characteristics of a chimeric monoclonal antibody, MOv18, reactive with an ovarian cancer-associated antigen. J Nucl Med. 1992;33(11):2000-2005. Cancer Control 69 115. Buist MR, Kenemans P, Molthoff CF, et al. Tumor uptake of intravenously administered radiolabeled antibodies in ovarian carcinoma patients in relation to antigen expression and other tumor characteristics. Int J Cancer. 1995;64(2):92-98. 116. van Zanten-Przybysz I, Molthoff CF, Roos JC, et al. Influence of the route of administration on targeting of ovarian cancer with the chimeric monoclonal antibody MOv18: i.v. vs. i.p. Int J Cancer. 2001;92(1):106-114. 117. Welshinger M, Yin BW, Lloyd KO. Initial immunochemical characterization of MX35 ovarian cancer antigen. Gynecol Oncol. 1997;67(2):188-192. 118. Yin BW, Kiyamova R, Chua R, et al. Monoclonal antibody MX35 detects the membrane transporter NaPi2b (SLC34A2) in human carcinomas. Cancer Immun. 2008;8:3. 119. Elgqvist J, Andersson H, Bäck T, et al. Alpha-radioimmunotherapy of intraperitoneally growing OVCAR-3 tumors of variable dimensions: outcome related to measured tumor size and mean absorbed dose. J Nucl Med. 2006;47(8):1342-1350. 120. Elgqvist J, Andersson H, Bernhardt P, et al. Administered activity and metastatic cure probability during radioimmunotherapy of ovarian cancer in nude mice with 211At-MX35 F(abʹ)2. Int J Radiat Oncol Biol Phys. 2006;66(4):1228-1237. 121. Elgqvist J, Andersson H, Jensen H, et al. Repeated intraperitoneal alpha-radioimmunotherapy of ovarian cancer in mice. J Oncol. 2010;2010:394913. 122. Andersson H, Cederkrantz E, Bäck T, et al. Intraperitoneal alphaparticle radioimmunotherapy of ovarian cancer patients: pharmacokinetics and dosimetry of (211)At-MX35 F(abʹ)2 — a phase I study. J Nucl Med. 2009; 50(7):1153-1160. 123. Jacobs AJ, Fer M, Su FM, et al. A phase I trial of a rhenium 186-labeled monoclonal antibody administered intraperitoneally in ovarian carcinoma: toxicity and clinical response. Obstet Gynecol. 1993;82(4 pt 1):586-593. 124. Turner JH, Rose AH, Glancy RJ, et al. Orthotopic xenografts of human melanoma and colonic and ovarian carcinoma in sheep to evaluate radioimmunotherapy. Br J Cancer. 1998;78(4):486-494. 125. Kievit E, Pinedo HM, Schlüper HM, et al. Comparison of monoclonal antibodies 17-1A and 323/A3: the influence of the affinity on tumour uptake and efficacy of radioimmunotherapy in human ovarian cancer xenografts. Br J Cancer. 1996;73(4):457-464. 126. Davies Q, Perkins AC, Roos JC, et al. An immunoscintigraphic evaluation of the engineered human monoclonal antibody (hCTMO1) for use in the treatment of ovarian carcinoma. Br J Obstet Gynaecol. 1999;106(1):31-37. 127. Molthoff CF, Pinedo HM, Schlüper HM, et al. Influence of dose and schedule on the therapeutic efficacy of 131I-labelled monoclonal antibody 139H2 in a human ovarian cancer xenograft model. Int J Cancer. 1992;50(3):474-480. 128. Knör S, Sato S, Huber T, et al. Development and evaluation of peptidic ligands targeting tumour-associated urokinase plasminogen activator receptor (uPAR) for use in alpha-emitter therapy for disseminated ovarian cancer. Eur J Nucl Med Mol Imaging. 2008;35(1):53-64. 129. Song EY, Abbas Rizvi SM, Qu CF, et al. Pharmacokinetics and toxicity of (213)Bi-labeled PAI2 in preclinical targeted alpha therapy for cancer. Cancer Biol Ther. 2007;6(6):898-904. 130. Steffen AC, Almqvist Y, Chyan MK, et al. Biodistribution of 211At labeled HER-2 binding affibody molecules in mice. Oncol Rep. 2007;17(5):1141-1147. 131. Tolmachev V, Orlova A, Pehrson R, et al. Radionuclide therapy of HER2-positive microxenografts using a 177Lu-labeled HER2-specific Affibody molecule. Cancer Res. 2007;67:2773-2782. 132. Moertel CG, Childs DS Jr, Reitemeier RJ, et al. Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet. 1969;2:865-867. 133. Gold DV, Alisauskas R, Sharkey RM. Targeting of xenografted pancreatic cancer with a new monoclonal antibody, PAM4. Cancer Res. 1995;55:1105-1110. 134. Mariani G, Molea N, Bacciardi D, et al. Initial targeting, biodistribution and pharmacokinetics screening of the monoclonal antibody PAM4 for immunoscintigraphy in patients with pancreatic cancer. Cancer Res. 1995;55:5911s-5915s. 135. Gold DV, Vardi Y, Ying Z, et al. Radioimmunotherapy of experimental pancreatic cancer with 131I-labeled PAM4 antibody. Int J Cancer. 1997;71:660-667. 136. Cardillo TM, Ying Z, Gold DV. Therapeutic advantage of 90yttriumversus 131iodine-labeled PAM4 antibody in experimental pancreatic cancer. Clin Cancer Res. 2001;7:3186-3192. 137. Gold DV, Schutsky K, Modrak D, et al. Low-dose radioimmunotherapy (90Y-PAM4) combined with gemcitabine for the treatment of experimental pancreatic cancer. Clin Cancer Res. 2003;9:3929S-3937S. 138. Gulec SA, Cohen SJ, Pennington KL, et al. Treatment of advanced pancreatic carcinoma with 90Y-Clivatuzumab Tetraxetan: a phase I singledose escalation trial. Clin Cancer Res. 2011;17:4091-4100. 139. Goldsmith S, Manzone T, Holt M, et al. Final results of a phase I/II study of 90Y-clivatuzumab tetraxetan (90Y-hPAM4) plus gemcitabine (Gem) in advanced pancreatic cancer (APC). J Nucl Med. 2012;53(suppl 1). Abstract 495. 140. Wegener WA. A study of fractionated 90Y-hPAM4 plus gemcitabine 70 Cancer Control in pancreatic cancer patients receiving at least 2 prior therapies. http://clinicaltrials.gov/ct2/show/NCT01510561. Accessed November 12, 2012. 141. Nordenstedt H, White DL, El-Serag HB. The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis. 2010;42:S206-S214. 142. Finn RS. Development of molecularly targeted therapies in hepatocellular carcinoma: where do we go now? Clin Cancer Res. 2010;16:390-397. 143. Liu YK, Yang KZ, Wu YD, et al. Treatment of advanced primary hepatocellular carcinoma by 131-I-anti-AFP. Lancet. 1983;1:531-532. 144. Sitzmann JV, Abrams R. Improved survival for hepatocellular cancer with combination surgery and multimodality treatment. Ann Surg. 1993;217:149. 145. Shi L, Wu M, Chen H. Radioimmunoimaging (RII) and radioimmunotherapy (RIT) of human primary hepatic cancer (hPHC) with anti-PHC monoclonal antibody in tumor-bearing nude mice. Zhonghua Zhong Liu Za Zhi. 1995;17:20-23. 146. Chen S, Li B, Xie H, et al. Phase I clinical trial of targeted therapy using 131I-Hepama-1 mAb in patients with hepatocellular carcinoma. Cancer Biother Radiopharm. 2004;19:589-600. 147. Chen Z-N, Mi L, Xu J, et al. Targeting radioimmunotherapy of hepatocellular carcinoma with iodine (131I) metuximab injection: clinical phase I/ II trials. Int J Radiat Oncol Biol Phys. 2006;65:435-444. 148. Zhang Z, Bian H, Feng Q, et al. Biodistribution and localization of iodine-131-labeled metuximab in patients with hepatocellular carcinoma. Cancer Biol Ther. 2006;5:318-322. 149. Kalofonos HP, Pawlikowska TR, Hemingway A, et al. Antibody guided diagnosis and therapy of brain gliomas using radiolabeled monoclonal antibodies directed against epidermal growth factor receptor and placental alkaline phosphatase. J Nucl Med. 1989;30:1636-1645. 150. Qin DX, Zheng R, Tang J, et al. Influence of radiation on the bloodbrain barrier and optimum time of chemotherapy. Int J Radiat Oncol Biol Phys. 1990;19:1507-1510. 151. Quang TS, Brady LW. Radioimmunotherapy as a novel treatment regimen: 125I-labeled monoclonal antibody 425 in the treatment of highgrade brain gliomas. Int J Radiat Oncol Biol Phys. 2004;58:972-975. 152. Cao Y, Tsien CI, Shen Z, et al. Use of magnetic resonance imaging to assess blood-brain/blood-glioma barrier opening during conformal radiotherapy. J Clin Oncol. 2005;23:4127-4136. 153. Wikstrand CJ, Fung KM, Trojanowski JQ, et al. Immunohistochemistry and antigens of diagnostic significance. In: Bigner DD, McLendon RE, Bruner JM, eds. Russell and Rubinstein’s Pathology of the Nervous System. 6th ed. New York, NY: Oxford University Press; 1998:251-304. 154. Riva P, Arista A, Sturiale C, et al. Treatment of intracranial human glioblastoma by direct intratumoral administration of 131I-labelled anti-tenascin monoclonal antibody BC-2. Int J Cancer. 1992;51:7-13. 155. Riva P, Arista A, Tison V, et al. Intralesional radioimmunotherapy of malignant gliomas. An effective treatment in recurrent tumors. Cancer. 1994;73:1076-1082. 156. Riva P, Arista A, Franceschi G, et al. Local treatment of malignant gliomas by direct infusion of specific monoclonal antibodies labeled with 131I: comparison of the results obtained in recurrent and newly diagnosed tumors. Cancer Res. 1995;55:5952-5956. 157. Riva P, Franceschi G, Frattarelli M, et al. Loco-regional radioimmunotherapy of high-grade malignant gliomas using specific monoclonal antibodies labeled with 90Y: a phase I study. Clin Cancer Res. 1999;5:3275s-3280s. 158. Riva P, Franceschi G, Riva N, et al. Role of nuclear medicine in the treatment of malignant gliomas: the locoregional radioimmunotherapy approach. Eur J Nucl Med. 2000;27:601-609. 159. 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. 1998;16:2202-2212. 160. Cokgor I, Akabani G, Kuan CT, et al. Phase I trial results of iodine131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with newly diagnosed malignant gliomas. J Clin Oncol. 2000;18:3862-3872. 161. 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. 2002;20:1389-1397. 162. Akabani G, Reardon DA, Coleman RE, et al. Dosimetry and radiographic analysis of 131I-labeled anti-tenascin 81C6 murine monoclonal antibody in newly diagnosed patients with malignant gliomas: a phase II study. J Nucl Med. 2005;46:1042-1051. 163. Reardon DA, Akabani G, Coleman RE, et al. 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. J Clin Oncol. 2006;24:115-122. 164. Reardon DA, Quinn JA, Akabani G, et al. Novel human IgG2b/murine chimeric antitenascin monoclonal antibody construct radiolabeled with 131I and administered into the surgically created resection cavity of patients with malignant glioma: phase I trial results. J Nucl Med. 2006;47:912-918. 165. Marquez A, Wu R, Zhao J, et al. Evaluation of epidermal growth factor receptor (EGFR) by chromogenic in situ hybridization (CISH) and immunohistochemistry (IHC) in archival gliomas using bright-field microscopy. Diagn Mol Pathol. 2004;13(1):1-8. 166. Brady LW, Markoe AM, Woo DV, et al. Iodine125 labeled anti-epiderJanuary 2013, Vol. 20, No. 1 mal growth factor receptor-425 in the treatment of malignant astrocytomas: a pilot study. J Neurosurg Sci. 1990;34:243-249. 167. Brady LW, Miyamoto C, Woo DV, et al. Malignant astrocytomas treated with iodine-125 labeled monoclonal antibody 425 against epidermal growth factor receptor: a phase II trial. Int J Radiat Oncol Biol Phys. 1992; 22:225-230. 168. Li L, Quang TS, Gracely EJ, et al. A Phase II study of anti-epidermal growth factor receptor radioimmunotherapy in the treatment of glioblastoma multiforme. J Neurosurg. 2010;113:192-198. 169. Kramer K, Cheung NK, Humm JL, et al. Targeted radioimmunotherapy for leptomeningeal cancer using (131)I-3F8. Med Pediatr Oncol. 2000;35:716-718. 170. Kramer K, Humm JL, Souweidane MM, et al. Phase I study of targeted radioimmunotherapy for leptomeningeal cancers using intra-Ommaya 131-I-3F8. J Clin Oncol. 2007;25:5465-5470. 171. Mason DY, Biberfeld P. Technical aspects of lymphoma immunohistology. J Histochem Cytochem. 1980;28:731-745. 172. Taylor CR. Immunohistologic studies of lymphomas: new methodology yields new information and poses new problems. J Histochem Cytochem. 1979;27:1189-1191. 173. Epstein AL, Chen F-M, Taylor CR. A novel method for the detection of necrotic lesions in human cancers. Cancer Res. 1988;48:5842-5848. 174. Epstein AL, Chen D, Ansari A, et al. Radioimmunodetection of necrotic lesions in human tumors using I-131 labeled TNT-1 F(abʹ)2 monoclonal antibody. Antibody Immunoconjugates Radiopharm. 1991;4:151-161. 175. Chen S, Yu L, Jiang C, et al. Pivotal study of iodine-131-labeled chimeric tumor necrosis treatment radioimmunotherapy in patients with advanced lung cancer. J Clin Oncol. 2005;23:1538-1547. 176. Patel SJ, Shapiro WR, Laske DW, et al. Safety and feasibility of convection-enhanced delivery of Cotara for the treatment of malignant glioma: initial experience in 51 patients. Neurosurgery. 2005;56:1243-1252. 177. Street HH, Goris ML, Fisher GA, et al. Phase I study of 131I-chimeric (ch) TNT-1/B monoclonal antibody for the treatment of advanced colon cancer. Cancer Biother Radiopharm. 2006;21:243-256. 178. Yu L, Chen T, Li Z, et al. 131I-ch-TNT-3 radioimmunotherapy of 43 patients with advanced lung cancer. Cancer Biother Radiopharm. 2006;21:5-14. 179. Anderson PM, Wiseman GA, Lewis BD, et al. A phase I safety and imaging study using radiofrequency ablation (RFA) followed by 131I-chTNT1/B radioimmunotherapy adjuvant treatment of hepatic metastases. Cancer Ther. 2003;1:297-306. 180. Wang H, Cao C, Li B, et al. Immunogenicity of iodine 131 chimeric tumor necrosis therapy monoclonal antibody in advanced lung cancer patients. Cancer Immunol Immunother. 2008;57(5):677-684. 181. Finkelstein SE, Fishman M. Clinical opportunities in combining immunotherapy with radiation therapy. Front Oncol. 2012;2:169. Epub 2012 November 26. January 2013, Vol. 20, No. 1 Cancer Control 71