Summary of systemic targeted radionuclide therapy symposium.
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Antibodies, Monoclonal↗
Biomedical subjects
Ruby F Meredith
Publications and source records attributed to Ruby F Meredith.
Systemic Targeted Radionuclide Therapy symposium introduction.
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Neoplasms↗
Pretargeted radioimmunotherapy.
This brief review covers the concept of pretargeted radioimmunotherapy and summarize the results obtained in preclinical animal models and initial phase I clinical trials. Reagents studied have been a bifunctional antibody prepared by crosslinking Fab' fragments from two antibodies with different specificity, one binding the target antigen expressed on tumors and the other binding a radiolabeled peptide. The alternative system is a conjugate of streptavidin linked to the pretargeting agent and radiolabeled biotin. After reaching optimal tumor targeting of the pretargeting agent, a synthetic mono-biotin poly N-acetyl-galactosamine compound was used to clear unbound targeting agent from the circulation before the injection of radiolabeled biotin. Promising therapeutic responses were obtained in various tumor xenograft models in athymic nude mice. A phase I study of an anti-CD20/streptavidin pretargeting agent and 15 mCi/m(2)(90)Y-biotin produced objective responses with minimal toxicity among lymphoma patients, with an average tumor-to-whole-body radiation dose ratio of 49. Pretargeting radioimmunotherapy approaches have shown higher tumor-to-whole-body ratios than that usually obtained with one-step radioimmunotherapy.
Animals↗
Clinical development of radioimmunotherapy for B-cell non-Hodgkin's lymphoma.
Over the past several decades, several biomolecules have been investigated for their ability to deliver radiation to cancer cells, but antibodies have been the carriers of choice in systemic targeted radionuclide therapy (STaRT). Two radioimmunotherapy agents that target the CD20 antigen, (131)I-tositumomab and (90)Y-ibritumomab tiuxetan, have been approved by the U.S. Food and Drug Administration for the treatment of patients with relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL), and clinical trials have shown that they are effective as monotherapies in the salvage setting, producing response rates that are often higher and durations of response that are often longer than those with chemotherapy. Escalated doses of these agents can be supported with stem cell transplantation and can produce high rates of complete response and greater survival in patients with relapsed NHL. The quality and duration of responses are greater with radioimmunotherapy when it is used earlier in the course of treatment.
Antibodies, Monoclonal↗
Ongoing investigations and new uses of radioimmunotherapy in the treatment of non-Hodgkin's lymphoma.
Studies in radiation oncology are focusing on the optimal use of systemic targeted radionuclide therapy (STaRT) in the treatment of patients with cancer. The two approved radioimmunotherapy agents, yttrium-90 ibritumomab tiuxetan and iodine-131 tositumomab, are being studied in a range of lymphoid malignancies, from low-grade to aggressive B-cell non-Hodgkin's lymphomas. Studies of standard- and escalated-dose radioimmunotherapy with or without stem cell support are reviewed, as are radioimmunotherapy with other therapeutic modalities in these settings. The results of these trials have important implications for clinical practice, and it is hoped that they will further clarify the optimal timing and dosing of these agents.
Antibodies, Monoclonal↗
Overview of dosimetry for Systemic Targeted Radionuclide Therapy (STaRT).
The purposes of systemic targeted radionuclide therapy dosimetry include compiling a database of normal organ radiation-absorbed doses that are carrier- and radionuclide-specific, and assuring that the normal organ radiation doses are within a safe range before therapy. Also of importance is quantitation of radiation delivery to tumors vs. normal tissues to correlate absorbed dose with tumor control. For agents with significant and variable excretion, estimates of individual patient distribution/clearance may be needed to optimize the dose-response relationship.
Brain↗
Logistics of therapy with the ibritumomab tiuxetan regimen.
Radioimmunotherapy is an important new modality for treating patients with B-cell non-Hodgkin's lymphoma (NHL). Clinical trials have shown the safety and efficacy of agents that deliver radiation directly to malignant cells by attaching the (131)I or (90)Y radionuclide to monoclonal antibodies against CD20. In clinical trials, (90)Y ibritumomab tiuxetan has produced rates of response as high as 83% in patients with relapsed or refractory CD20+ NHL. The ibritumomab tiuxetan regimen is conveniently given in an outpatient setting over the course of 7-9 days. This article describes the logistics for initiating treatment, coordinating a multidisciplinary team, identifying eligible patients, and delivering the imaging and therapeutic doses of ibritumomab tiuxetan. The standard radiation safety procedures to protect family members and healthcare professionals involved in the care of patients treated with (90)Y ibritumomab tiuxetan are also reviewed. Treatment with the ibritumomab tiuxetan regimen involves only standard precautions needed to minimize radiation exposure to other persons.
Antibodies, Monoclonal↗
166Ho-DOTMP radiation-absorbed dose estimation for skeletal targeted radiotherapy.
UNLABELLED: 166Ho-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonate (DOTMP) is a tetraphosphonate molecule radiolabeled with 166Ho that localizes to bone surfaces. This study evaluated pharmacokinetics and radiation-absorbed dose to all organs from this beta-emitting radiopharmaceutical. METHODS: After two 1.1-GBq administrations of 166Ho-DOTMP, data from whole-body counting using a gamma-camera or uptake probe were assessed for reproducibility of whole-body retention in 12 patients with multiple myeloma. The radiation-absorbed dose to normal organs was estimated using MIRD methodology, applying residence times and S values for 166Ho. Marrow dose was estimated from measured activity retained after 18 h. The activity to deliver a therapeutic dose of 25 Gy to the marrow was determined. Methods based on region-of-interest (ROI) and whole-body clearance were evaluated to estimate kidney activity, because the radiotracer is rapidly excreted in the urine. The dose to the surface of the bladder wall was estimated using a dynamic bladder model. RESULTS: In clinical practice, gamma-camera methods were more reliable than uptake probe-based methods for whole-body counting. The intrapatient variability of dose calculations was less than 10% between the 2 tracer studies. Skeletal uptake of 166Ho-DOTMP varied from 19% to 39% (mean, 28%). The activity of 166Ho prescribed for therapy ranged from 38 to 67 GBq (1,030-1,810 mCi). After high-dose therapy, the estimates of absorbed dose to the kidney varied from 1.6 to 4 Gy using the whole-body clearance-based method and from 8.3 to 17.3 Gy using the ROI-based method. Bladder dose ranged from 10 to 20 Gy, bone surface dose ranged from 39 to 57 Gy, and doses to other organs were less than 2 Gy for all patients. Repetitive administration had no impact on tracer biodistribution, pharmacokinetics, or organ dose. CONCLUSION: Pharmacokinetics analysis validated gamma-camera whole-body counting of 166Ho as an appropriate approach to assess clearance and to estimate radiation-absorbed dose to normal organs except the kidneys. Quantitative gamma-camera imaging is difficult and requires scatter subtraction because of the multiple energy emissions of 166Ho. Kidney dose estimates were approximately 5-fold higher when the ROI-based method was used rather than the clearance-based model, and neither appeared reliable. In future clinical trials with 166Ho-DOTMP, we recommend that dose estimation based on the methods described here be used for all organs except the kidneys. Assumptions for the kidney dose require further evaluation.
Aged↗
Clinically useful marrow dosimetry for targeted radionuclide therapy.
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Bone Marrow↗
Pretargeted radioimmunotherapy (RIT) with a novel anti-TAG-72 fusion protein.
Pretargeted radioimmunotherapy (RIT) increases the dose of radionuclide delivered to tumor sites while limiting radiation to normal tissues. The three components in Pretarget include a streptavidin-containing targeting molecule, a synthetic clearing agent (sCA), and (90)Y and/or (111)In-DOTA-biotin. This trial determined the feasibility and safety of using a genetically engineered fusion protein directed to TAG-72 as the targeting agent. Nine (9) patients with metastatic colorectal cancer (TAG-72+) received 160 mg/m(2) of CC49Fusion protein intravenously (i.v.), followed by the sCA, 45 mg/m(2) i.v. Twenty-four (24) hours later, patients received radiolabeled DOTA-biotin (either 0.65 or 1.3 mg/m(2)). All patients received 5 mCi of (111)In-DOTA-biotin for imaging and dosimetry purposes and patients 4-9 received 10 mCi/m2 of (90)Y-DOTA-biotin as well. The mean plasma T1/2 of CC49Fusion protein was 23 +/- 6 hours. Greater than 95% of the circulating CC49Fusion protein was eliminated from the circulation within 6 hours of sCA administration. The radiolabeled DOTA-biotin rapidly localized to tumor sites while the unbound fraction was rapidly excreted. The mean tumor-to-marrow radiation dose ratio was 139:1 and mean tumor: whole body was 56:1. No infusion-related, renal, hepatic, or hematologic toxicities were noted. CC49Fusion protein performs well in a pretargeted RIT schema, and further study with escalating doses of (90)Y should be pursued. This strategy has the potential to deliver effective radiation tumor doses to TAG- 72+ tumors.
Adenocarcinoma↗
Phase I study of 90Y-CC49 monoclonal antibody therapy in patients with advanced non-small cell lung cancer: effect of chelating agents and paclitaxel co-administration.
PURPOSE: This trial was designed to evaluate strategies to improve the efficacy of a radiolabeled monoclonal antibody (mCC49) against tumor-associated glycoprotein-72 (TAG-72) in patients with non-small cell lung cancer (NSCLC). The aims of this study were to determine: safety and maximum tolerated dose (MTD) of (90)Y-mCC49 in combination with interferon alpha2beta (IFN); whether calcium disodium versonate (EDTA) or diethylenetriamine penta-acetic acid (DTPA) could reduce myelosuppression; and safety and MTD of paclitaxel (Taxol) in combination with (90)Y-mCC49. EXPERIMENTAL DESIGN: Patients with advanced (TAG-72 positive) non-small cell lung cancer were entered in three phases; the first was the dose escalation of a single agent (90)Y-mCC49. In the second phase, the dose escalation of (90)Y-mCC49 was attempted with concurrent EDTA or DTPA chelator therapy. In the third phase, radiosensitization with a continuous infusion of paclitaxel (96-hour) was administered with (90)Y-mCC49. All patients received IFN for TAG-72 up-regulation. RESULTS: Thirty-four patients were evaluable. Reversible Grade 4 neutropenia and thrombocytopenia were the dose-limiting toxicities (DLTs). The MTD of (90)Y-mCC49/IFN was 14 mCi/m(2). EDTA did not alter toxicity, while there was a modest reduction of myelosuppression with DTPA. The MTD of continuous infusion paclitaxel in combination with 14 mCi/m(2) of (90)Y-CC49 was 60 mg/m(2). There were no objective tumor responses. CONCLUSIONS: (90)Y-mCC49/IFN was well tolerated at a dose of 14 mCi/m(2). The clinical effect of adjunctive chelating therapy with DTPA was modest. The MTD of coadministered continuous infusion (96-hour) paclitaxel was 60 mg/m(2). Because of the immunogenicity of the murine compound, future studies are planned using a humanized version of CC49.
Adult↗
Patient-specific dosimetry of pretargeted radioimmunotherapy using CC49 fusion protein in patients with gastrointestinal malignancies.
UNLABELLED: Pretargeted radioimmunotherapy (RIT) using CC49 fusion protein, comprised of CC49-(scFv)4 and streptavidin, in conjunction with 90Y/111In-DOTA-biotin (DOTA = dodecanetetraacetic acid) provides a new opportunity to improve efficacy by increasing the tumor-to-normal tissue dose ratio. To our knowledge, the patient-specific dosimetry of pretargeted 90Y/111In-DOTA-biotin after CC49 fusion protein in patients has not been reported previously. METHODS: Nine patients received 3-step pretargeted RIT: (a) 160 mg/m2 of CC49 fusion protein, (b) synthetic clearing agent (sCA) at 48 or 72 h later, and (c) 90Y/111In-DOTA-biotin 24 h after the sCA administration. Sequential whole-body 111In images were acquired immediately and at 2-144 h after injection of 90Y/111In-DOTA-biotin. Geometric-mean quantification with background and attenuation correction was used for liver and lung dosimetry. Effective point source quantification was used for spleen, kidneys, and tumors. Organ and tumor 90Y doses were calculated based on 111In imaging data and the MIRD formalism using patient-specific organ masses determined from CT images. Patient-specific marrow doses were determined based on radioactivity concentration in the blood. RESULTS: The 90Y/111In-DOTA-biotin had a rapid plasma clearance, which was biphasic with <10% residual at 8 h. Organ masses ranged from 1,263 to 3,855 g for liver, 95 to 1,009 g for spleen, and 309 to 578 g for kidneys. The patient-specific mean 90Y dose (cGy/37 MBq, or rad/mCi) was 0.53 (0.32-0.78) to whole body, 3.75 (0.63-6.89) to liver, 2.32 (0.58-4.46) to spleen, 7.02 (3.36-11.2) to kidneys, 0.30 (0.09-0.44) to lungs, 0.22 (0.12-0.34) to marrow, and 28.9 (4.18-121.6) to tumors. CONCLUSION: Radiation dose to normal organs from circulating radionuclide is substantially reduced using pretargeted RIT. Tumor-to-normal organ dose ratios were increased about 8- to 11-fold compared with reported patient-specific mean dose to liver, spleen, marrow, and tumors from 90Y-CC49.
Aged↗
Blood-based red marrow dosimetry: where's the beef?
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Adult↗
Phase 1 trial of a novel anti-CD20 fusion protein in pretargeted radioimmunotherapy for B-cell non-Hodgkin lymphoma.
Pretargeted radioimmunotherapy (PRIT) has the potential to increase the dose of radionuclide delivered to tumors while limiting radiation to normal tissues. The purpose of this phase 1 trial is to assess safety of this multistep approach using a novel tetrameric single-chain anti-CD20-streptavidin fusion protein (B9E9FP) as the targeting moiety in patients with B-cell non-Hodgkin lymphoma (NHL), and to characterize its pharmacokinetics and immunogenicity. All patients received B9E9FP (160 mg/m(2) or 320 mg/m(2)); either 48 or 72 hours later, a synthetic clearing agent (sCA) was administered (45 mg/m(2)) to remove circulating unbound B9E9FP. (90)Yttrium ((90)Y; 15 mCi/m(2))/(111)In (5 mCi)-DOTA-biotin was injected 24 hours later. There were 15 patients enrolled in the study. B9E9FP had a mean plasma half-life (T(1/2)) of 25 +/- 6 hours with a reduction in plasma level of more than 95% within 6 hours of sCA administration. (90)Y/(111)In-DOTA-biotin infusion resulted in rapid tumor localization and urinary excretion. The ratio of average tumor to whole-body radiation dose was 49:1. No significant hematologic toxicities were noted in 12 patients. There were 2 patients who had hematologic toxicity related to progressive disease. There were 2 complete remissions (90 and 325 days) and one partial response (297 days). B9E9FP performs well as the targeting component of PRIT with encouraging dosimetry, safety, and efficacy. A dose escalation trial of (90)Y-DOTA-biotin in this format is warranted.
Adult↗
Bone marrow dosimetry using blood-based models for radiolabeled antibody therapy: a multiinstitutional comparison.
UNLABELLED: Standardization of marrow dosimetry is of considerable importance when estimating dose-response for a multicentered clinical trial involving radionuclide therapy. However, it is only within the past five years that the intercomparison of marrow dosimetry results among separate clinical trials that use the same agent has become scientifically feasible. In this work, we have analyzed reported marrow dosimetry results from radioimmunotherapy trials and recalculated marrow absorbed doses at a central facility using a standard blood model with patient-specific source data. The basic approach used in the American Association of Physicists in Medicine (AAPM)/Sgouros marrow dosimetry methodology was common to calculation performed at all participating institutions, including the central facility. Differences in dose estimates associated with starting assumptions and the exact implementation of the AAPM/Sgouros calculation methodology used by the source institutions and the central facility were quantified and compared. METHODS: Data from 22 patients enrolled in radiolabeled antibody clinical trials were randomly selected from 7 participating institutions for the assessment of marrow dose. The analysis was restricted to those patients who were treated with 131I- or 186Re-labeled antibody and had no marrow involvement. Calculation of bone marrow dose at each participating institution was unique to the trial or institution, but all used some form of the AAPM/Sgouros blood model approach. The central facility adopted a marrow dosimetry model based on the AAPM/Sgouros model for radiolabeled antibodies using the standard MIRD approach to the remainder-of-body contribution. A standardized approach to account for variations in patient mass was used for the remainder-of-body component. To simplify clinical implementation, regional marrow uptake and time-dependent changes in the marrow-to-blood concentration ratio were not included. Methods of formatting the collection of standard datasets useful in defining dose-response parameters are also presented. RESULTS: Bone marrow doses were calculated according to the method described for each of the 22 patients based on the patient-specific data supplied by the participating institutions. These values were then individually compared with the marrow doses originally reported by each institution. Comparison of the two calculation methods was expressed as a ratio of the marrow doses for each patient. The mean ratio for the dose estimates at the participating institution calculation compared with the central laboratory value was 0.920 +/- 0.259 (mean +/- SD), with a range from 0.708 to 1.202. CONCLUSION: The independent use of the AAPM/Sgouros method blood model approach to marrow dosimetry has brought these dose estimates to within 30% of the results obtained centrally compared with substantially higher uncertainties reported previously. Variations in calculation methodology or initial assumptions adopted by individual institutions may still contribute significant uncertainty to dose estimates, even when the same data are used as a starting point for the calculation comparison shown here. A clinically relevant, standard method for marrow dosimetry for radiolabeled antibodies is proposed as a benchmark for intercomparison purposes. A parameter sensitivity analysis and a summary discussion of the use of this model for potentially improving dose-response data correlation are also presented.
Adult↗
P105 as a prognostic indicator in patients irradiated for locally advanced head-and-neck cancer: a clinical/laboratory correlative analysis of RTOG-9003.
PURPOSE: In a previous retrospective study, p105 AD, a proliferation-associated nuclear antigen density (AD), was found to be an independent prognostic factor for patients irradiated for locally advanced head-and-neck cancer. We sought to confirm this finding by analyzing patients entered on RTOG 9003, a Phase III randomized trial of altered fractionation radiotherapy. METHODS AND MATERIALS: Paraffin blocks of pretreatment biopsies of the primary tumor of patients with Stage III or IV squamous cell carcinoma of the oral cavity, oropharynx, or supraglottic larynx, or Stage II squamous cell carcinoma of the hypopharynx or base of tongue entered on RTOG 9003 were prospectively collected at patient entry. From these paraffin blocks, areas of tumor were selected based on histologic examinations and sectioned. Nuclear suspensions were then prepared and processed for p105 antibody and DNA staining. Flow cytometric quantification of p105 labeling indices and DNA content were then performed for correlation with local-regional control and survival. RESULTS: Paraffin blocks of tumor biopsies from 457 of 1073 patients entered were available for p105 determination. There was no significant difference in pretreatment characteristics between patients who had paraffin blocks available or not available. The median (range) of p105 labeling index (LI-C), p105 labeling index of cells in S phase (p105 LI-S), and p105 AD were 56 (range: 6-99), 8.255 (range: 0.913-23), and 67 (range: 5-364), respectively. Multivariate analysis of prognostic factors showed that T stage, N stage, Karnofsky performance status, and fractionation schedule were significant for local-regional control (p < 0.0001, 0.0011, <0.0001, and 0.007, respectively) and T stage, N stage, Karnofsky performance status, and tumor grade were significant for survival (p = 0.018, 0.002, <0.0001, and 0.0058, respectively). Neither p105 LI-C nor p105 LI-S nor p105 AD nor DNA ploidy was significant for local-regional control or survival. CONCLUSION: p105 labeling indices, antigen density, and DNA ploidy do not predict the outcome of patients irradiated for advanced squamous cell carcinomas of the head and neck.
Antigens, Neoplasm↗
Phase III quality-of-life study results: impact on patients' quality of life to reducing xerostomia after radiotherapy for head-and-neck cancer--RTOG 97-09.
PURPOSE: To determine whether prevention of hyposalivation after curative radiotherapy (RT) to the head and neck improves patients' quality of life (QOL). METHODS AND MATERIALS: Patients were to receive at least 50 Gy to 50% of the volume of the major salivary glands, provide unstimulated and stimulated saliva samples, and complete the University of Washington head-and-neck QOL tool before RT and 3 and 6 months after RT. Patients were randomized to receive pilocarpine 5 mg or placebo q.i.d. RESULTS: A total of 249 patients was randomized between March 1998 and January 2000. Of these, 214 were eligible for QOL analysis. Patients were evenly distributed between arms by race, gender, tobacco use, tumor site, T stage (50% T2-T3), and salivary function. A Karnofsky performance status of 90% was more common in the pilocarpine arm. Twenty percent of the patients on the pilocarpine arm and 29% of the patients on the placebo arm were taking nutritional supplements. The placebo arm patients had greater mouth pain and chewing difficulties. Compliance for the QOL tool at 3 and 6 months was 65% and 50%, respectively. Despite statistically significant (p = 0.047 and p = 0.049, respectively) preservation of salivary function in the pilocarpine arm, patients on the pilocarpine arm reported difficulties with swallowing (75%), activity (80%), hyposalivation (64%), and taste (81%). No difference was noted between arms at 3 months in mucositis scores, with both arms demonstrating increased requirement for oral nutrients. CONCLUSION: Objective prevention of hyposalivation did not affect patients' assessment of salivary function or QOL because of the greater impact mucositis plays in QOL after RT.
Female↗
Comparison of methods for predicting myelotoxicity for non-marrow targeting I-131-antibody therapy.
Although marrow suppression is usually the dose-limiting toxicity in non-marrow ablative radionuclide therapy, calculated marrow dose has rarely been used for prescribing the radioactivity to be administered. This study assesses the correlation of myelotoxicity with mCi/m(2), patient-specific lean body dose, marrow dose from blood and body of reference man, or from blood and body using the patient-specific mass. Fourteen prostate cancer patients were treated with (131)I-CC49. Radioactivity in blood and body was determined and used to calculate their contributions to the marrow dose. Platelet nadir expressed as percentage (%) of the initial baseline was used as an indicator for myelotoxicity. Correlation between platelet nadir (%) and myelotoxicity predictors was evaluated. Platelet nadirs (%) varied substantially (5-33%) for a small range of injected radioactivity/m(2) (68-78 mCi/m(2), 2.5-2.9 GBq/m(2)). Patient-specific total body dose based on lean body mass exhibited a weak correlation (r = 0.48) with platelet nadir. Marrow dose from blood and body of reference man had a better correlation (r = 0.73). Patient-specific marrow dose from blood and body (or lean body) had a similar correlation (r = 0.74 or 0.73). Radioactivity in the remainder of the body contributed only 28% of the total dose, and thus changes to this dose component had small impact on total marrow dose. Marrow dose was a better predictor for myelotoxicity than mCi/m(2) or lean total body dose in this non-marrow targeting (131)I-antibody therapy with high blood contributions to total dose.
Antigens, Neoplasm↗