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The field of medicine has been rapidly changing recently for providers and patients. This article considers how such changes have impacted the roles and responsibilities of the medical facility radiation safety officer. To supplement the personal experiences of the authors, a questionnaire soliciting voluntary feedback was submitted to a group of medical radiation safety officers. Several common themes emerged in the responses received, confirming that the role of the medical radiation safety officer has indeed changed concurrent with the changes occurring in medicine, frequently due to changing regulations and accreditation requirements in response to new and novel imaging and treatment modalities. Today's medical radiation safety officer faces some daunting challenges, including limited staffing, incorporation of numerous accreditation standards, and maintenance of effective communication with administrators and other personnel. Nonetheless, respondents indicate that they have tremendous job satisfaction and embrace the changing landscape. Shared challenges and changes are discussed herein to provide readers with a perspective on the life of a medical center radiation safety officer.

Recent world events have increased concern that hospitals must be prepared for radiological emergencies. Emergency departments (EDs) must be ready to treat patients suffering from injuries in combination with radiation exposure or contamination with radioactive material. Every hospital should have a Radiological Emergency Medical Response Plan, tested through periodic drills, which will allow effective handling of contaminated and injured patients. Treatment of life-threatening or severe traumatic injuries must take priority over radiation-related issues. The risk to ED staff from radioactive contamination is minimal if universal precautions are used. The likelihood of significant radiation exposure to staff under most circumstances is small. Educating medical staff on the magnitude of the radiological hazards allows them to promptly and confidently provide the necessary patient care. Measures must be taken to prevent the "worried well" and uninjured people with radioactive contamination from overwhelming the ED.

Radioimmunotherapy (RIT) has been hampered by delivery of only a small fraction of the administered dose of radiolabeled MAb to tumor. A strategy for creating and controlling tumor vascular permeability would enable more effective RIT. The alpha v beta 3 integrin receptor is an appealing target for strategies designed to enhance permeability of tumor vessels because it is highly and preferentially expressed in most tumors. In human tumor mouse models, apoptosis of neovascular endothelial cells has been demonstrated after treatment with alpha v beta 3 antagonists. Since this apoptotic effect could transiently increase permeability of tumor blood vessels, radiolabeled antibodies (MAb) circulating during this period would have increased access to extravascular tumor. To determine if this hypothesis was correct, a pharmacokinetic study of an immunospecific MAb given after an alpha v beta 3 antagonist was performed in nude mice bearing human breast cancer xenografts. The alpha v beta 3 antagonist, cyclic RGD pentapeptide (c-RGDf-ACHA; cyclo arginine glycine aspartic acid D-phenylalanine -1 amino cyclohexane carboxylic acid), inhibits alpha v beta 3 binding to its vitronectin ligand at nanomolar levels. Cyclic RGD peptide (250 micrograms i.p.) given 1 hour before 111In-ChL6 MAb resulted in a 40-50% increase in tumor uptake (concentration), when compared to the control tumor uptake, of MAb 24 hours after administration. When cyclic RGD peptide was given as a continuous infusion (17.5 micrograms/hr) for 1 or 24 hours before 111In-ChL6, tumor uptake of 111In-ChL6 was increased less, and, these data were not statistically different from the control data. There were no differences for any of the groups in the groups in the concentrations of 111In-ChL6 in normal organs or blood when compared to the control group. The results suggest that cyclic RGD peptide provided a temporary, selective increase in tumor vascular permeability, that allowed a larger fraction of the 111In-ChL6 to accumulate in the tumor.

In order to improve radioimmunotherapy of lymphoma, a Lym-1 single-chain antigen-binding (scFv) protein molecule was produced. Because the commonly used polymerase chain reaction (PCR) method frequently causes unexpected mutations, we developed a non-PCR method for scFv gene assembly. The method involved a stepwise linkage of doubly-restricted DNA fragments and re-digestion of the resultant concatamers. Using this strategy, the Lym-1 scFv expression gene was readily constructed without mutations. The recombinant gene was cloned into an expression vector and scFv protein was expressed. The method can be used for other genes or DNA recombination.

BACKGROUND Radioimmunotherapy (RIT) is a promising new modality for targeted, systemic delivery of radionuclides specifically to sites of androgen-independent metastatic prostate cancer. To be effective, RIT requires an antibody with specificity for malignant cells and appropriate pharmacokinetics in the body. METHODS Specific binding of the L6 monoclonal antibody to prostate cancer cell lines or cell lysates was determined by enzyme-linked immunoabsorbent assay (ELISA), solid-phase radioimmunoassay, and immunofluorescent staining. Biodistribution, tumor uptake, and whole body and blood clearances of 125I-L6 were determined in nude mice bearing human prostate cancer xenografts. RESULTS The L6 monoclonal antibody showed strong binding to the lysates of PC3 and DU145 prostate cancer cell lines, and 66% binding to live PC3 cells. The L6 antibody specifically targeted prostate cancer in PC3 and DU145-tumored nude mice, where approximately 10% of the injected dose of 125I-L6 bound to prostate cancer. Low-normal organ uptake was found, and the blood clearances were similar in each group of tumored mice. CONCLUSIONS The L6 monoclonal antibody targets human prostate cancer xenografts in nude mice and has low-normal organ uptake. Therefore, further study of the radiolabeled L6 monoclonal antibody for RIT of prostate cancer is warranted. Prostate 37:91–97, 1998. © 1998 Wiley-Liss, Inc.

PURPOSE Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced remissions in patients with non-Hodgkin's lymphoma (NHL) when labeled with iodine 131 ((131)I). Based on the strategy of fractionating the total dose, this study was designed to define the maximum-tolerated dose (MTD) and efficacy of the first two, of a maximum of four, doses of (131)I-Lym-1 given 4 weeks apart. Additionally, toxicity and radiation dosimetry were assessed. MATERIALS AND METHODS Twenty patients with advanced NHL entered the study a total of 21 times. Thirteen (62%) of the 21 entries had diffuse large-cell histologies. All patients had disease resistant to standard therapy and had received a mean of four chemotherapy regimens. (131)I-Lym-1 was given after Lym-1 and (131)I was escalated in cohorts of patients from 40 to 100 mCi (1.5 to 3.7 GBq)/m2 body surface area. RESULTS Mean radiation dose to the bone marrow from body and blood (131)I was 0.34 (range, 0. 1 6 to 0.63) rad/mCi (0.09 mGy/MBq; range, 0.04 to 0.17 mGy/ MBq). Dose-limiting toxicity was grade 3 to 4 thrombocytopenia with an MTD of 100 mCi/m2 (3.7 GBq/m2) for each of the first two doses of (131)I-Lym-1 given 4 weeks apart. Nonhematologic toxicities did not exceed grade 2 except for one instance of grade 3 hypotension. Ten (71 %) of 14 entries who received at least two doses of (131)I-Lym-1 therapy and 11 (52%) of 21 total entries responded. Seven of the responses were complete, with a mean duration of 14 months. All three entries in the 100 mCi/m2 (3.7 MBq/m2) cohort had complete remissions (CRs). All responders had at least a partial remission (PR) after the first therapy dose of (131)I-Lym-1. CONCLUSION (131)I-Lym-1 induced durable remissions in patients with NHL resistant to chemotherapy and was associated with acceptable toxicity. The nonmyeloablative MTD for each of the first two doses of (131)I-Lym-1 was 100 mCi/m2 (total, 200 mCi/m2) (3.7 GBq/m2; total, 7.4 GBq/m2).

Monoclonal antibodies were raised against yttrium(III)-1, 4, 7, 10-tetraazacyclododecane-N,N',N''N'''--tetraacetic acid (Y-DOTA) and copper(II)-1, 4, 8, 11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (Cu-TETA). Four hybridomas with high Y-DOTA binding activity and one hybridoma with Cu-TETA activity were selected. MAbs were purified from mouse ascites by Protein A affinity chromatography and characterized. Affinity constants were determined by equilibrium dialysis and the highest affinity Y-DOTA MAb (K(aff) = 1.9 x 10(8) M(-1)) was further characterized by competitive ELISA. Gd-DOTA competed as well as Y-DOTA, whereas In-DOTA required 740x higher concentrations for 50% inhibition of this Y-DOTA MAb binding to human serum albumin-Y-DOTA-coated microtiter plates. These anti-metal chelate MAbs have potential use as vehicles for the pretargeted delivery of radiometal chelates to tumors.

A patient with aggressive, chemotherapy-resistant non-Hodgkins lymphoma (NHL) was treated with 131I-Lym-1, a mouse antibody, on a protocol designed for serial therapy. Human anti-mouse antibody (HAMA) developed within 1 month of initial therapy. The patient also developed an antibody to the hypervariable region of the Lym-1 antibody (Lym-1 specific). Because the patient was responding to therapy, plasmaphoresis was used to reduce the level of HAMA followed by unlabeled Lym-1 calculated to be sufficient to block residual HAMA. This allowed additional therapy on three subsequent occasions over 5 months. Despite very high HAMA levels, no untoward effects from administrations of Lym-1 were observed. The HAMA response of the patient included anti-Lym-1 specific antibodies containing anti-idiotypic antibodies. The anti-Lym-1 antibody level has been sustained over the 9 year interval since 131I-Lym-1 therapy and has been associated with a uniquely long remission of the patient's disease. These observations demonstrate that, under certain circumstances, radioimmunotherapy (RIT) can be given safely and effectively despite HAMA. Anti-idiotypic antibodies could have induced an immune cascade that contributed to the prolonged disease-free survival of the patient.

BACKGROUND Because most patients with advanced non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) respond to radioimmunotherapy (RIT), the study was designed to evaluate the relationship between response and survival in patients treated with radiolabeled Lym-1. METHODS Fifty-seven patients with NHL (52) or CLL (5) were treated with radiolabeled Lym-1 antibody between 1985 and 1994. Influence of response to treatment on survival was examined directly and was also adjusted for other factors previously found to be significant predictors of survival. A multivariate model that was based on baseline Karnofsky performance status (KPS) and serum lactic dehydrogenase (LDH) predicted response and survival and was used to define risk groups. Proportional-hazards, Kaplan-Meier, and Landmark models were used to evaluate parameters for their ability to predict outcome. RESULTS By using a proportional-hazards model with response as a time-dependent variable, overall response (P < 0.001) and complete response (P = 0.006) were predictive of increased survival in univariate analyses. Overall response continued to be significant (P = 0.02) in multivariate analyses, even when risk groups that also predicted survival were included. Median survival of responders was 84 weeks, whereas that of nonresponders was 22 weeks when the Landmark method, based on response status at 16 weeks from start of therapy, was used to generate survival curves. CONCLUSIONS Response to treatment with radiolabeled Lym-1 was associated with increased survival, even when adjusted for baseline clinical parameters that also predicted for survival. The results provide the first unbiased evidence for survival effects of RIT in patients. Cancer 1997; 80:2706-11. © 1997 American Cancer Society.

BACKGROUND. The beneficial effects of radioimmunotherapy (RIT) may result from activation of molecular pathways that lead to programmed cell death (apoptosis). The influences of sequence and timing of 99 Y-DOTA-peptide-ChL6 antibody ( 90 Y-ChL6) and anti-epidermal growth factor receptor antibody (ch225) or paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) on efficacy and toxicity were examined. METHODS. Groups of human breast carcinoma (HBT 3477) tumored mice received paclitaxel (300 or 600 μg) or ch225 (70, 150, or 350 μg) at various intervals before or after 90 Y-ChL6. Mortality, hematologic toxicity, weight loss, and therapeutic efficacy were evaluated. RESULTS. Mice receiving paclitaxel within 24 hours of 90 Y-ChL6 had a 100% response rate; 48% were cured when paclitaxel was given 6 or 24 hours after 90 Y-ChL6. When 150 μg ch225 was given 24 hours before 90 Y-ChL6, the response and cure rates surpassed those of 90 Y-ChL6 alone. Timing of administration was critical, with mortality rates as high as 80% in some groups receiving 350 μg ch225 and 90 Y-ChL6. CONCLUSIONS. In this aggressive human breast carcinoma model, combined 90 Y-ChL6 and paclitaxel had a high therapeutic index with many cures. Sequence of administration was critical in order for ch225 or paclitaxel, when combined with 90 Y-ChL6, to enhance the response rate.

Synergistic multimodality therapy is needed for breast cancer. Breast cancer frequently has p53 mutations that result in cells less likely to undergo apoptosis when exposed to DNA damaging therapies. Taxol (paclitaxel) is more effective in the presence of mutant p53. 90 Y-labeled DOTA-peptide-ChL6 ( 90 Y-ChL6, where ChL6 is chimeric L6 antibody and DOTA is 1,4,7,10-tetraazacyclododecane- N,N ′, N ", N ‴-tetraacetic acid) is a novel radioimmunoconjugate for targeting radiation to cancer. It has a stable metal chelator and a peptide linker that can be catabolized by hepatic lysozymes. This study was designed to assess potential synergism between Taxol and 90 Y-ChL6 in a highly anaplastic breast cancer model, HBT 3477. There was no tumor response in mice receiving ChL6 or Taxol alone. In mice receiving 90 Y-ChL6 alone, 79% (15 of 19) of tumors responded although none were cured. If Taxol was administered 24–72 hours before 90 Y-ChL6, again, 79% (23 of 29) of tumors responded but 21% were cured. When Taxol was administered 6 or 24 hours after 90 Y-ChL6, 100% (46 of 46) of tumors responded and 48% were cured. Taxol given with 90 Y-ChL6 did not substantially increase toxicity. Enhancement of the therapeutic effect when Taxol was added to 90 Y-ChL6 therapy for HBT 3477 xenografts was striking. The synergistic therapeutic effect of Taxol with 90 Y-ChL6 may relate to the p53 mutant status and BCL2 expression in HBT 3477 cells, observations that increase the likelihood that the results of this study are relevant to therapy for breast cancer in patients. In conclusion, Taxol seemed to be synergistic with 90 Y-ChL6 in this human breast cancer model. Up to 50% of these anaplastic breast cancer xenografts were cured by combined modality therapy.

Host development of human anti-mouse antibodies (HAMA) in response to administered antibodies has been reported as a problem for antibody imaging and therapy. However, radioimmunotherapy has been shown to be effective in patients with B-cell malignancies because their immunodeficient state precludes or delays development of a HAMA response to mouse antibodies. Baseline HAMA activity was assayed in 60 patients with B-lymphocytic non-Hodgkin's lymphoma or chronic lymphocytic leukemia and sequentially in 43 patients who were subsequently treated with radiolabeled Lym-1 antibody. Pre-existing “HAMA” activity was found in 3 (5%) of the 60 patients screened for treatment consideration. The incidence of development of HAMA in the 43 patients treated with multiple doses of radiolabeled Lym-1 antibody was 12 (28%). There was no evidence for an anaphylactoid or related response in the HAMA positive patients. HAMA activity interrupted therapy in 14% of the patients (6 of 43) but did not preclude therapeutic responses to radiolabeled Lym-1 therapy. Median survival for the HAMA positive patients was longer (18 months) than for those who did not develop HAMA activity (9 months).

Background. BrE-3 is a monoclonal antibody that has promise for imaging and therapy of human adenocarcinoma. Because of observations in therapeutic trials of yttrium-90 ( 90 Y) escape from radioimmunoconjugates and uptake by the skeleton with resultant bone marrow toxicity, the authors attempted to evaluate the importance of this factor by a comparison of the LD 50 in healthy mice treated with 90 Y that had been chelated with either of two high affinity chelators, methylbenzyldiethylenetriaminepentaacetic acid (MX-DTPA) or bromoacetamidobenzyl-1,4,7,10-tetraazocyclododecane-N,N',N'',N'''-tetra-acetic acid (BAD)

The radiation dose-limiting toxicity from radioimmunotherapy has been myelotoxicity in the absence of bone marrow reconstitution (transplantation). Myelotoxicity can be assessed directly by biopsy examination of the bone marrow and indirectly by peripheral blood counts. In patients with B-cell malignancies, thrombocytopenia has been the initial and most severe manifestation of 131 I-Lym-1 radiation toxicity from treatment. Manifestations of myelotoxicity varied greatly among the patients and from one treatment dose to another in the same patient, suggesting that additional factors were present. There was an increased likelihood of Grade 3-4 hematopoietic toxicity after 131 I-Lym-1 treatment if the patient had peripheral blood cell abnormalities before undergoing 131 I-Lym-1 treatment

Background. There has been little success in using radioimmunotherapy in patients with adenocarcinoma, partly because of the low tumor uptake of the administered monoclonal antibody (MoAb). The authors recently reported therapeutic response in advanced cancer patients who received 131 I chimeric-L6 MoAb. The L6 MoAb identifies abundant, nonshed antigen that is expressed in many human carcinomas, including carcinomas of the lung, breast, colon, and ovary. In vitro both mouse L6 (L6) and chimeric L6 (ChL6) mediate complement-dependent tumor cytolysis with human serum, and antibody-dependent tumor cell cytolysis with normal human peripheral blood mononuclear cells

Insight into the metabolism of radiolabeled antibodies is important for the design of better radioimaging and therapy agents. To test the effect of linkers that can be cleaved in vivo, we introduced Ala-Leu-Ala-Leu between the antibody Lym-1 and an 111In-labeled benzyl-EDTA. For comparison, we studied a conjugate without the linker. Digestion of the two conjugates in vitro showed that the one with Ala-Leu-Ala-Leu was cleaved rapidly by the liver protease cathepsin B1 (T1/2 approximately 6 h). After 100 h of digestion, reversed-phase HPLC product analysis of the Ala-Leu-Ala-Leu conjugate showed that 48% of the total radioactivity had the same retention time as (p-aminobenzyl)-EDTA(In), and 37% of the total radioactivity had the same retention time as [p-(Ala-Leu-amido)benzyl]-EDTA(In). After 97 h of digestion, the conjugate without the linker had 79% of the radioactivity activity still attached to the protein. We also tested the two conjugates in mice. Ala-Leu-Ala-Leu had only a moderate effect on the whole body and liver clearance in vivo. The excretion of the radioactivity was about 6% per day with the linker and about 3% per day without the linker. HPLC analysis of the urine of a single mouse showed products similar to the in vitro study; 54% of the excreted radioactivity had the same retention time as (p-aminobenzyl)-EDTA(In), while 10% had the retention time of [p-(Ala-Leu-amido)benzyl]-EDTA(In).

L-6, a mouse IgG2a anti-adenocarcinoma monoclonal antibody (MoAb) with favorable immunopathology and mouse biokinetics, was evaluated for cancer radioimmunotherapy by pharmacokinetic studies in 10 patients with breast cancer. The effect of escalating the preinfused protein dose was studied in two patients at each level, using 50, 100, 150, 200 and 400 mg of unlabeled L-6 prior to a 10 mCi imaging dose of 131I L-6. Quantitative imaging, and blood and urine clearances were obtained. After the 50 mg preinfusion, rapid blood clearance and lung extraction of the radiopharmaceutical occurred immediately post injection. Greater preload amounts of L-6 were associated with an increase in the intercept of the slow phase of the blood clearance from 17 to 22% injected dose (ID) with 50 mg to 70 to 80% ID with 400 mg (P less than 0.01). Lung uptake of the radiopharmaceutical immediately post injection decreased from 15 to 19% ID (50 mg) to 6 to 8% ID (400 mg). Tumors were visualized only after larger L-6 preloads, but in these patients small chest tumors contained 0.6-1.2% ID (0.1% ID/g maximum). This study suggests that L-6 reactive sites that are readily available in the lung can be saturated, so that a subsequent dose of I-131 L-6 is delivered to the tumor. This approach provides a new strategy for developing an effective method for radioimmunotherapy using a MoAb that has some cross-reactivity. Quantitative imaging contributed to detection of the cross-reactivity and the strategy for overcoming it.

Anti-CD20 monoclonal antibodies (mAbs), unlabeled rituximab (Rituxan, Biogen Idec Inc., Cambridge, MA; and Genentech Inc., South San Francisco, CA) or radiolabeled 90Y-ibritumomab (Zevalin, Biogen Idec Inc., Cambridge, MA) and 131I-tositumomab (Bexxar; Glaxo Smith Kline, Research Triangle Park, NC), have proven to be effective therapy for non-Hodgkin's lymphoma (NHL), but also induce immediate and persistent decreases in normal peripheral blood lymphocytes (PBLs). Lym-1, a mAb that selectively targets malignant lymphocytes, also has induced therapeutic responses and prolonged survival in patients with NHL when labeled with iodine-131 (131I). We have retrospectively examined its effect on PBLs in 41 NHL patients that had received 131I-Lym-1 therapy. Absolute lymphocyte counts (ALCs) were evaluated before and after the first and last 131I-Lym-1 infusion. Modest decreases in PBLs were observed in most of the patients. Using strict criteria to define recovery, time to recovery was determined for 19 patients, with the remainder censored because of insufficient follow-up (median follow up for censored patients: 22 days). Using Kaplan-Meier estimates, it would be predicted that 31% of patients would recover by 28 days and that median time to recovery would be 44 days after the last 131I-Lym-1 infusion. No predictors were found for time to recovery, considering such factors as the administered Lym-1 or 131I dose, spleen volume, or radiation doses to the body, marrow, or spleen. The data suggest that the effect of 131I-Lym-1 on ALC is the result of a nonspecific radiation effect, rather than a specific Lym-1 mAb effect. The shorter time required for ALC recovery after 131I-Lym-1 when compared to that reported for anti-CD20 mAbs, whether radiolabeled or otherwise, is probably related to differing mechanisms for lymphocytotoxicity and lesser Lym-1 antigenic density on normal B-lymphocytes.

The role of the Radiation Safety Officer at a medical facility can be complicated. The complexity of the position is based on the breadth of services provided at the institution and the nature of the radioactive materials license. Medical practices are constantly changing and the use of ionizing radiation continues to rise in this area. Some of the newer medical applications involving radiation have unique regulatory and safety issues that must be addressed. Oversight of the uses of radiation start at the local level (radiation safety officer, radiation safety committee) and are heavily impacted by outside agencies (i.e. Nuclear Regulatory Commission, State Radiologic Health, The Joint Commission (TJC), etc). This session will provide both an overview of regulatory oversight and essential compliance practices as well as practical ways to assess and introduce some of the new applications utilizing radioactive materials into your medical facility. Learning Objectives: Regulatory Compliance and Safety with New Radiotherapies: Spheres and Ra-223 (Lance Phillips) 1. Understand the radioactive materials license amendment process to add new radiotherapies (i.e., SIR-Spheres, Therasphere, Xofigo). 2. Understand the AU approval process for microspheres and Xofigo. 3. Examine the training and handling requirements for new procedures. 4. Understand the process involved with protocol development, SOP in order to define roles and responsibilities. The RSO and The RSC: Challenges and Opportunities (Colin Dimock) 1. Understand how to form an effective Committee. 2. Examine what the Committee does for the Program and the RSO. 3. Understand the importance of Committee engagement. 4. Discuss the balance of the complimentary roles of the RSO and the Committee. The Alphabet Soup of Regulatory Compliance: Being Prepared for Inspections (Linda Kroger) 1. Recognize the various regulatory bodies and organizations with oversight or impact in Nuclear Medicine, Radiology and Radiation Oncology. 2. Examine 10CFR35 requirements as they relate to the everyday practice of Nuclear Medicine and Radiation Oncology. 3. Understand the nature of available guidance documents (e.g., NUREG 1556). 4. Examine the commonalities between TJC and CMS preparedness.

The role of the Radiation Safety Officer at a medical facility can be complicated. The complexity of the position is based on the breadth of services provided at the institution and the nature of the radioactive materials license. Medical practices are constantly changing and the use of ionizing radiation continues to rise in this area. Some of the newer medical applications involving radiation have unique regulatory and safety issues that must be addressed. Oversight of the uses of radiation start at the local level (radiation safety officer, radiation safety committee) and are heavily impacted by outside agencies (i.e. Nuclear Regulatory Commission, State Radiologic Health, The Joint Commission (TJC), etc). This session will provide both an overview of regulatory oversight and essential compliance practices as well as practical ways to assess and introduce some of the new applications utilizing radioactive materials into your medical facility. Learning Objectives: Regulatory Compliance and Safety with New Radiotherapies: Spheres and Ra-223 (Lance Phillips) 1. Understand the radioactive materials license amendment process to add new radiotherapies (i.e., SIR-Spheres, Therasphere, Xofigo). 2. Understand the AU approval process for microspheres and Xofigo. 3. Examine the training and handling requirements for new procedures. 4. Understand the process involved with protocol development, SOP in order to define roles and responsibilities. The RSO and The RSC: Challenges and Opportunities (Colin Dimock) 1. Understand how to form an effective Committee. 2. Examine what the Committee does for the Program and the RSO. 3. Understand the importance of Committee engagement. 4. Discuss the balance of the complimentary roles of the RSO and the Committee. The Alphabet Soup of Regulatory Compliance: Being Prepared for Inspections (Linda Kroger) 1. Recognize the various regulatory bodies and organizations with oversight or impact in Nuclear Medicine, Radiology and Radiation Oncology. 2. Examine 10CFR35 requirements as they relate to the everyday practice of Nuclear Medicine and Radiation Oncology. 3. Understand the nature of available guidance documents (e.g., NUREG 1556). 4. Examine the commonalities between TJC and CMS preparedness.

Myelotoxicity can be ameliorated by peripheral blood stem cell (PBSC) infusion. Continuous irradiation by radioactivity retained in the body after high-dose radioimmunotherapy can damage PBSCs if they are transfused too early. Previously, infusion time was predetermined using the radioactivity concentration in the blood. This study proposes to plan PBSC infusion time based on noninvasive dosimetry that considers damage of PBSCs during PBSC circulation and residence in organs with high radioactivity.The method considers a time-varying distribution of PBSCs and radioactivity in tissues. Five breast cancer patients received (111)In-2IT-BAD-m170 for imaging, and 3 of the 5 received high doses of (90)Y-2IT-BAD-m170 therapy followed by PBSC infusion. (90)Y concentrations in tissues were extrapolated from quantitative imaging of (111)In, and (90)Y blood concentrations were determined from (90)Y in serial blood samples. The radiation dose to PBSCs was determined by time integration of the organ dose rate and PBSC distribution rate. The radiosensitivity of PBSCs was determined by measuring survival of granulocyte-macrophage colony-forming units with (90)Y in cell culture.The mean effective half-life of (90)Y within the imaging period (up to 6 d) was 3.7 d for liver, 2.4 d for spleen, 2.1 d for kidneys, 1.8 d for lungs, and 1.6 d for blood. The survival fractions of PBSCs in patients were determined as functions of the infusion time and the injected dose of (90)Y-2IT-BAD-m170. To achieve 90% PBSC survival rate for a 2.0-GBq injection dose, PBSC dosimetry suggested a time interval of 13 d after radioimmunotherapy for PBSC infusion. In contrast, the simple blood concentration method suggested an interval about 7 d for the same PBSC survival rate. In our clinical practice, an interval of 2 wk has been used and worked well.A noninvasive dosimetry method was developed for optimizing the time interval for PBSC infusion after high-dose radionuclide therapy. Our studies suggested that the PBSC dosimetry method was more effective than the blood concentration method in determining the optimal time to reinfuse PBSCs for radiopharmaceuticals that have much a higher activity concentration in organs than that in the blood.

The selection and characterization of anti-MUC-1 single-chain antibody fragments (scFv) is a first step toward the construction of new anticancer molecules designed for optimal blood clearance and tumor penetration. The mucin MUC-1 was chosen as an antigen because it is abundantly expressed on epithelial cancers in an aberrantly glycosylated form, making it structurally and antigenically distinct from MUC-1 expressed on normal cells.A previously constructed anti-MUC-1 phage display library from hyperimmunized mice, with 5 x 10(5) calculated variants, was screened for the selection of anti-MUC-1 scFvs. Selection criteria were high binding to a MUC-1 peptide containing 4 tandem repeats of 20 amino acids and to MUC-1-positive MCF-7 (human breast cancer) cell lysates in ELISA.Six anti-MUC-1 scFv clones were selected and characterized. Nucleotide sequencing showed that four of them were full length scFv genes (variable heavy chain + variable light chain), whereas the remaining two contained either a variable heavy chain or a variable light chain alone. Their binding affinities (K(a)) range between 8 x 10(7) and 10(9) M(-1). Immunohistopathology demonstrated reactivity with breast cancer cells (MCF-7 and BT20) and human breast biopsy tissue. Molecular modeling revealed high structural similarity of the anti-MUC-1 scFvs with the X-ray-determined structure of the anti-CEA scFv (MFE-23).In vitro antigen binding was demonstrated for the selected anti-MUC-1 scFvs. The binding affinities of these scFvs are in a promising range for efficient in vivo antigen binding. These anti-MUC-1 scFvs will be evaluated as antigen-binding modules in new multifunctional agents for the detection and therapy of cancer.

Immunotherapeutic approaches to cancer offer an attractive adjunct to conventional modalities, although human antiglobulin responses can be an obstacle to repeated treatment. This study of a large number of patients with B-cell malignancies, over an extended period of time, characterized their human antimouse antibody (HAMA) seroconversion.A total of 617 samples from 112 subjects were analyzed for HAMA titers. Eighty-five patients with B-cell malignancies; 12 breast cancer patients, and 15 volunteers were titered for comparison. Fifty-six B-cell malignancy patients were titered for HAMA throughout Lym-1 radioimmunotherapy (RIT); 29 were titered after a single imaging dose of Lym-1 antibody.Baseline titers did not correlate with subsequent HAMA seroconversion against Lym-1. Only 1 of 29 (3%) of the patients developed HAMA after an imaging dose of Lym-1. Of the RIT trial group, 37 of 56 (66%) never developed HAMA above baseline despite multiple doses. Of those who did (19 of 56; or 34%), the HAMA responses fell into two categories. Thirteen responded rapidly (median of 31 days) and were termed "early responders," whereas 6, termed "late responders," had a median response time of 111 days. Early responders developed higher peak HAMA titers with fewer exposures to Lym-1 and took longer to return to baseline than did the late responders. The frequency of new antiglobulin seroconversion decreased as the number of exposures increased.Seventy-seven percent of B-cell malignancy patients developed no response or a weak response after multiple doses of mouse Lym-1 antibody. Positive responders occurred in all histology types and fell into two categories differing in seroconversion time and titer, possibly indicative of the initial state of the immune system.

CD22 is a membrane glycophosphoprotein found on nearly all healthy B-lymphocytes and most B-cell lymphomas. Recent in vitro studies have identified several anti-CD22 monoclonal antibodies (mAbs) that block the interaction of CD22 with its ligand. One of these mAbs, HB22.7, has been shown to effectively induce apoptosis in several B-cell lymphoma cell lines. Lymphoma xenograft studies with Raji-xenograft mice were used to assess the toxicity and efficacy of HB22.7 alone and with combined modality immunotherapy (CMIT) with yttrium 90Y-DOTA-peptide-Lym-1 radioimmunotherapy (RIT). The effect of the sequence of these agents on the combined treatment was assessed by administering HB22.7 24 hours before, simultaneously with, or 24 hours after RIT. Within the groups treated with RIT alone or with RIT and HB22.7 (CMIT), the reduction in tumor volume was the greatest when HB22.7 was administered simultaneously with and 24 hours after RIT, and in the RIT treatment groups, this translated into the greatest overall response and survival, respectively. Overall survival rates at the end of the 84-day CMIT trial were 67% and 50% in the groups treated with HB22.7 simultaneously and 24 hours after RIT, respectively. This compared favorably with the untreated and the RIT alone groups, which had survival rates of 38% and 43% at the end of the trial. Surprisingly, when compared with untreated controls and all other treatment groups, the greatest cure and overall survival rates were observed in the group treated with HB22.7 alone, with 47% cured and 76% surviving at the end of the 84-day trial. RIT clearance was not affected by treatment with HB22.7. When compared with RIT alone, there was no significant additional hematologic (white blood cell, red blood cell, or platelet count) toxicity when HB22.7 was added to RIT. Nonhematologic toxicity (assessed as change in body weight) was also unchanged when HB22.7 was added to RIT. Thus the anti-CD22 ligand-blocking antibody HB22.7 has independent lymphomacidal properties and augments the efficacy of90Y-DOTA-peptide-Lym-1 in lymphoma xenografts without significant toxicity.

Radioimmunotherapy using radiolabeled monoclonal antibodies against tumor-associated antigens has been efficacious, particularly in the treatment of radiosensitive malignancies such as lymphoma. Antilymphoma monoclonal antibody Lym-1, labeled with copper-67 ( 67 Cu), iodine-131 ( 131 I), or yttrium-90 ( 90 Y), has been effective salvage therapy for patients with non-Hodgkin's lymphoma. Although 131 I has had the dominant role in radioimmunotherapy thus far, several properties of radiometals are preferable. A total of 70 patients with B-lymphocytic non-Hodgkin's lymphoma were studied using 67 Cu-2IT-BAT-Lym-1, 131 I-Lym-1, or 111 In-2IT-BAD-Lym-1. Because 90 Y does not have good emissions for imaging, indium-111 ( 111 In), its analogue, was used as a surrogate to estimate 90 Y-2IT-BAD-Lym- 1 pharmacokinetics and radiation dosimetry. Subsets of four patients in each group received 67 Cu- and 131 I-labeled Lym-1 or 111 In- and 131 I-labeled Lym-1, allowing direct comparisons of the radioimmunoconjugates. Sequential blood samples and planar images were used to quantitate radioimmunoconjugate in tissues in order to determine pharmacokinetics and radiation dosimetry. 67 Cu-2IT-BAT-Lym-1 and 90 Y-2IT-BAD-Lym-1 exhibited higher cumulated activity concentrations and radiation absorbed doses per unit of administered radioactivity for tumors than did 131 I-Lym-1. The mean tumor cumulated activity (area under the time-activity curve) concentrations per unit of administered radioactivity for 67 Cu-2IT-BAT-Lym-1, 131 I-Lym-1, and 90 Y-2IT-BAD-Lym-1 were 96.89, 33.96, and 43.42 GBq-s/GBq/g, respectively. The mean tumor radiation doses from 67 Cu-2IT-BAT-Lym-1, 131 I-Lym-1, and 90 Y-2IT-BAD-Lym-1 were 2.5, 1.0, and 6.6 Gy/GBq, respectively, because 90 Y deposits more radiation per unit of administered radioactivity. Per unit of administered radioactivity, radiation doses from 67 Cu-2IT-BAT-Lym-1 and 131 I-Lym-1 to normal tissues were similar except that the liver received a higher dose from 67 Cu-2IT-BAT-Lym-1 than from 131 I-Lym-1; radiation doses to normal tissues from 90 Y-2IT-BAD-Lym-1 were generally higher. Consequently, the therapeutic indices (ratio of radiation doses to tumor and normal tissues) for 67 Cu-2IT-BAT-Lym-1, and less generally for 90 Y- 2IT-BAD-Lym-1, were more favorable when compared to those for 131 I-Lym-1. Data from the matched subsets of patients showed similar therapeutic indices to those for the groups of patients. 67 Cu-2IT-BAT-Lym-1 showed more potential than 131 I-Lym-1 or 90 Y-2IT-BADLym- 1 for non-Hodgkin's lymphoma radioimmunotherapy

Despite low radiation dose rates, radioimmunotherapy (RIT) has proven particularly effective in the treatment of malignancies, such as lymphoma. Apoptosis has been suggested to be a major mechanism for cell death from continuous low-dose rate radiation from radioimmunotherapy. The goal of this study was to examine Raji lymphoma xenografts for induction of apoptosis and modulation of apoptosis-related gene and protein expression in response to 67Cu-2IT-BAT-Lym-1 RIT. In preclinical and clinical trials, 67Cu-2IT-BAT-Lym-1 has shown an exceptionally long tumor residence time associated with substantial cumulated radiation doses. The Raji model mirrors human lymphomas that have mutant p53 and increased BCL2 expression. Untreated athymic BALB/c nu/nu mice and mice treated with 400 micrograms Lym-1, or 335-500 microCi 67Cu on less than 400 micrograms Lym-1 antibody, were observed for toxicity and response over 84 days. Subgroups of 4-5 mice were sacrificed at 3, 6 and 24 h after therapy so that tumors could be examined for poly(ADP-ribose) polymerase (PARP) and DNA ladder evidence for apoptosis and for BCL2, p53, p21, GADD45, TGF-beta 1 and c-MYC gene and protein expression. Untreated tumors had little evidence of apoptosis and Lym-1 had no effect on apoptosis or gene expression. 67Cu-2IT-BAT-Lym-1 RIT induced an overall response rate of 50% with tolerable toxicity, and 29% of the tumors were cured at cumulated tumor radiation doses of about 1800 cGy. Apoptosis was greatly increased in the RIT treated Raji xenografts as evidenced by cleavage of PARP to the characteristic 85 kD fragment at 3 and 6 h and by the DNA cleavage pattern. BCL2 gene and protein expression were substantially decreased at 3 and 24 h, respectively, after 67Cu-2IT-BAT-Lym-1 RIT despite only modest cumulated radiation doses (56 cGy at 3 h). Evidence for apoptosis preceded tumor regression by 4-6 days. In these therapy-resistant, human lymphoma tumors treated with 67Cu-2IT-BAT-Lym-1, apoptosis was convincingly demonstrated to be a major mechanism for the effectiveness of RIT and occurred by p53-independent mechanisms.

PURPOSE This trial was conducted to assess the toxicity and efficacy of 131I-Lym-1 in patients with either malignant B-cell non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) using low-dose, fractionated radioimmunotherapy (RIT). MATERIALS AND METHODS Thirty adult patients who had advanced B-cell malignancies (25 NHL and 5 CLL) had progressed despite standard therapy; 12 patients entered the trial with Karnofsky performance status (KPS) of equal to or greater than 60. Patients were treated with a series of intravenous doses of 131I-Lym-1 with a goal of reaching a cumulative dose in each patient of at least 300 mCi. All patients were Lym-1 reactive. Clinical responses and immediate toxicity were evaluable in all 30 patients and delayed toxicity in 26. RESULTS Toxicity to Lym-1 antibody occurred with 28% of the 176 doses and was transient. Human antimouse antibodies (HAMA) were generated in 30% after a mean of 4 doses, but interrupted therapy in only 10% of the patients. Thrombocytopenia was dose-limiting; there were no deaths due to toxicity. Tumor regression occurred in 25 (83%) of the patients and was great enough, and durable enough, in 17 (57%) to qualify them as responders; 13 NHL patients and 4 CLL patients. Advanced disease often interrupted therapy prematurely. However, 18 patients received at least 180 mCi of 131I-Lym-1; 17 (94%) of these responded to the therapy. CONCLUSION Although advanced disease often interrupted therapy prematurely, the results from 131I-Lym-1 therapy are clearly promising and warrant additional trials.

Standard therapy for AIDS associated NHL (AANHL) is toxic and often ineffective. Radioimmunotherapy (RIT) is an appealing alternative to chemotherapy because of the radiosensitivity of NHL and the ability of the Lym-1 monoclonal antibody to target therapeutic irradiation to NHL while relatively sparing normal tissue. A Phase I/II study of 90Y-2IT-BAD-Lym-1 was designed specifically for RIT of AANHL. The first patient has been treated with 15 mCi (7.5 mCi/m2) of 90Y-2IT-BAD-Lym-1, after an imaging dose of 111In-2IT-BAD-Lym-1. Before RIT, AANHL in the maxillary sinus extended into the oral cavity and axillary adenopathy was present. Imaging showed excellent accumulation of 111In-2IT-BAD-Lym-1 in the tumors. Substantial shrinkage of the oral lymphoma was observed 18 hours after the therapy dose of 90Y-2IT-BAD-Lym-1 and axillary adenopathy had disappeared by one week after RIT. Transient Grade IV myelosuppression was the only notable toxicity. Further RIT cycles were precluded by development of an antibody response (HAMA) against Lym-1. This novel preliminary study has shown that Lym-1 can target AANHL and produce significant tumor regression thereby providing encouragement to proceed with additional patients.

Radioimmunotherapy (RIT), a therapy targeted to tumor cells, is a modality that can currently deliver radiation to tumor cells at levels 3–50-times higher than to the normal tissue with the next highest dose. RIT appears promising for future cancer therapy. Clinical responses in patients with advanced cancer have frequently been achieved with RIT as a single agent. Extended complete remissions and even increased survival have been achieved in lymphoma. Similar results in other cancers seem likely with RIT in combination therapy.

Lym-1, a monoclonal antibody (MAb) that preferentially targets malignant lymphocytes, has induced therapeutic remissions in patients with advanced non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) when labeled with iodine-131 (131I). Based on the strategy of fractionating the total radiation dose, trials were designed to define the safety, toxicity, and efficacy of a series of doses of 131I-Lym-1 given 2-6 weeks apart. All patients had disease resistant to standard therapy. 131I-Lym-1 was given after unconjugated Lym-1 and the 131I dose was escalated in Phase I-II trials. Therapy proved safe. The dose-limiting toxicity was thrombocytopenia. Nonhematological toxicities did not exceed grade 2 except for infrequent instances of grade 3 hypotension. In a low-dose (LD) trial of 131I-Lym-1, tumor regression occurred in 25 (83%) of 30 patients and 17 (57 %) had durable remissions; 3 of the remissions were complete. In a maximum tolerated dose (MTD) trial of 131I-Lym-1, 10 (71%) of 14 entries that received at least two doses of 131I-Lym-1 therapy and 11 (52%) of 21 total entries had remissions; 7 of the remissions were complete. All 3 entries in the MTD cohort of 100 mCi/m2 [3.7 MBq/m2] of body surface area had durable complete remissions. Therapeutic remission and human anti-mouse antibody (HAMA) after Lym-1 therapy were associated with increased survival that was significant in multivariate analyses. Evidence for an Ab3 idiotypic network with an antibody cytotoxic for Raji human lymphoma was found in the only patient examined in detail thus far; this patient was studied because she had a high titer, HAMA and prolonged survival. In conclusion, 131I-Lym-1 induced durable remissions in patients with chemotherapy-resistant NHL or CLL and was associated with acceptable toxicity. In a subset of the patients, survival was quite prolonged perhaps related to development of Ab3.

Radioimmunolocalization for detection or therapy of breast cancer has undergone only limited investigation. Successful targeting of breast tumors with radiolabeled antibodies has awaited the identification of the optimal antigen targets, the appropriate antibodies, as well as the linking chemistry necessary to produce stable radioimmunoconjugates. Radioimmunodetection trials in breast cancer have employed both the intravenous and interstitial administration routes. Sensitivity of intravenously administered immunoconjugates for metastatic disease has ranged from 50-78% in small series of patients 1-3. The antibodies used in these trials were directed against various breast cancer associated antigens including human milk fat globule membrane (HMFG) or breast epithelial mucin and CEA. Excellent sensitivity for primary breast tumors using an antibody directed against TAG-72 has been reported3, but in the same patients