Accurate quantitation of activity provides the basis for internal dosimetry of targeted radionuclide therapies. This study investigated quantitative imaging capabilities at sites with a variety of experience and equipment and assessed levels of errors in activity quantitation in Single-Photon Emission Computed Tomography (SPECT) and planar imaging. Participants from 9 countries took part in a comparison in which planar, SPECT and SPECT with X ray computed tomography (SPECT-CT) imaging were used to quantify activities of four epoxy-filled cylinders containing 133Ba, which was chosen as a surrogate for 131I. The sources, with nominal volumes of 2, 4, 6 and 23mL, were calibrated for 133Ba activity by the National Institute of Standards and Technology, but the activity was initially unknown to the participants. Imaging was performed in a cylindrical phantom filled with water. Two trials were carried out in which the participants first estimated the activities using their local standard protocols, and then repeated the measurements using a standardized acquisition and analysis protocol. Finally, processing of the imaging data from the second trial was repeated by a single centre using a fixed protocol. In the first trial, the activities were underestimated by about 15% with planar imaging. SPECT with Chang's first order attenuation correction (Chang-AC) and SPECT-CT overestimated the activity by about 10%. The second trial showed moderate improvements in accuracy and variability. Planar imaging was subject to methodological errors, e.g., in the use of a transmission scan for attenuation correction. The use of Chang-AC was subject to variability from the definition of phantom contours. The project demonstrated the need for training and standardized protocols to achieve good levels of quantitative accuracy and precision in a multicentre setting. Absolute quantification of simple objects with no background was possible with the strictest protocol to about 6% with planar imaging and SPECT (with Chang-AC) and within 2% for SPECT-CT.

The reliability of radiation dose estimates in internal radionuclide therapy is directly related to the accuracy of activity estimates obtained at each imaging time point. The recently published MIRD pamphlet no. 23 provided a general overview of quantitative SPECT imaging for dosimetry. The present document is the first in a series of isotopespecific guidelines that will follow MIRD 23 and focuses on one of the most commonly used therapeutic radionuclides, 131I. The purpose of this document is to provide guidance on the development of protocols for quantitative 131I SPECT in radionuclide therapy applications that require regional (normal organs, lesions) and 3-dimensional dosimetry.

Cancer Biotherapy & RadiopharmaceuticalsVol. 25, No. 5 Letters to the EditorRenal DosimetryBarry W. Wessels, Roger G. Dale, Marta Cremonesi, Ruby F. Meredith, Alan J. Green, Bertrand Brill, Wesley E. Bolch, George Sgouros, and Stephen R. ThomasBarry W. WesselsDepartment of Radiation Oncology, Case Western Reserve University School of Medicine, and University Hospitals Case Medical Center, Cleveland, Ohio.Search for more papers by this author, Roger G. DaleRadiation Physics and Radiobiology, Imperial Healthcare NHS Trust, London, United Kingdom.Search for more papers by this author, Marta CremonesiMedical Physics Division, European Institute of Oncology, Milan, Italy.Search for more papers by this author, Ruby F. MeredithUniversity of Alabama at Birmingham, Birmingham, Alabama.Search for more papers by this author, Alan J. GreenCRC Targeting and Imaging Group, Dept. of Oncology, Royal Free and University College Medical School, University College London, London, United Kingdom.Search for more papers by this author, Bertrand BrillDepartment of Radiology, Vanderbilt University, Nashville, Tennessee.Search for more papers by this author, Wesley E. BolchDepartment of Nuclear and Radiological Engineering, University of Florida, Gainesville, Florida.Search for more papers by this author, George SgourosDepartment of Radiology and Radiological Sciences, School of Medicine, The Johns Hopkins University, Baltimore, Maryland.Search for more papers by this author, and Stephen R. ThomasDepartment of Radiology, University of Cincinnati, Cincinnati, Ohio.Search for more papers by this authorPublished Online:15 Oct 2010https://doi.org/10.1089/cbr.2010.0867AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited byIndividualized Dosimetry of Kidney and Bone Marrow in Patients Undergoing 177 Lu-DOTA-Octreotate Treatment7 December 2012 | Journal of Nuclear Medicine, Vol. 54, No. 1Early prediction of tumour response to PRRT21 August 2013 | Nuklearmedizin, Vol. 52, No. 5Renal Dosimetry: Ready for Biological Equivalent Dose? Response to Medical Internal Radiation Dose and European Association of Nuclear Medicine Committee Letters Jeffry A. Siegel, Michael G. Stabin, and Robert M. Sharkey5 January 2011 | Cancer Biotherapy & Radiopharmaceuticals, Vol. 25, No. 6Something More than Estimating Renal Dosimetry Lisa Bodei, Marta Cremonesi, and Giovanni Paganelli5 January 2011 | Cancer Biotherapy & Radiopharmaceuticals, Vol. 25, No. 6 Volume 25Issue 5Oct 2010 InformationCopyright 2010, Mary Ann Liebert, Inc.To cite this article:Barry W. Wessels, Roger G. Dale, Marta Cremonesi, Ruby F. Meredith, Alan J. Green, Bertrand Brill, Wesley E. Bolch, George Sgouros, and Stephen R. Thomas.Renal Dosimetry.Cancer Biotherapy and Radiopharmaceuticals.Oct 2010.597-599.http://doi.org/10.1089/cbr.2010.0867Published in Volume: 25 Issue 5: October 15, 2010Online Ahead of Print:September 28, 2010PDF download

Purpose: There is a need for new treatments for Hodgkin and T-cell lymphoma due to the development of drug resistance in a proportion of patients. This phase I study of radioimmunotherapy used CHT-25, a chimeric antibody to the α-chain of the interleukin-2 receptor, CD25, conjugated to iodine-131 (131I) in patients with refractory CD25-positive lymphomas. Experimental Design: Fifteen patients were treated (Hodgkin lymphoma, 12; angioimmunoblastic T-cell lymphoma, 1; adult T-cell leukemia/lymphoma, 2). Tumor was monitored by computed tomography and in all but two patients by 18F-fluorodeoxyglucose positron emission tomography. Results: There were no grade 3 or 4 infusion reactions. At the maximum tolerated dose of 1,200 MBq/m2, the major side effect was delayed myelotoxicity with the nadir for platelets at 38 days and for neutrophils at 53 days. One patient treated with 2,960 MBq/m2 developed prolonged grade 4 neutropenia and thrombocytopenia and died of Pneumocystis jiroveci pneumonia. Nonhematologic toxicity was mild. Single photon emission computer tomography imaging showed tumor-specific uptake and retention of 131I and no excessive retention in normal organs. Of nine patients receiving ≥1,200 MBq/m2, six responded (three complete response and three partial response); one of six patients with administered radioactivity of ≤740 MBq/m2 had a complete response. Conclusions: CHT-25 is well tolerated with 1,200 MBq/m2 administered radioactivity and shows clinical activity in patients who are refractory to conventional therapies. Phase II studies are justified to determine efficacy and toxicity in a broader range of clinical scenarios. (Clin Cancer Res 2009;15(24):7701–10)

Purpose: In preclinical models, radioimmunotherapy with 131I-A5B7 anti–carcinoembryonic antigen (CEA) antibody (131I-A5B7) combined with the vascular disruptive agent combretastatin-A4-phosphate (CA4P) produced cures unlike either agent alone. We conducted a phase I trial determining the dose-limiting toxicity (DLT), maximum tolerated dose, efficacy, and mechanism of this combination in patients with gastrointestinal adenocarcinomas. Experimental Design: Patients had CEA of 10 to 1,000 μg/L, QTc ≤450 ms, no cardiac arrhythmia/ischaemia, and adequate hematology/biochemistry. Tumor was suitable for blood flow analysis by dynamic contrast enhanced-magnetic resonance imaging (MRI). The starting dose was 1,800 MBq/m2 of 131I-A5B7 on day 1 and 45 mg/m2 CA4P given 48 and 72 hours post-131I-A5B7, then weekly for up to seven weeks. Results: Twelve patients were treated, with mean age of 63 years (range, 32-77). Two of six patients at the first dose level had DLTs (grade 4 neutropenia). The dose was reduced to 1,600 MBq/m2, and CA4P escalated to 54 mg/m2. Again, two of six patients had DLTs (neutropenia). Of ten assessable patients, three had stable disease and seven had progressive disease. Single-photon emission computed tomography confirmed tumor antibody uptake in all 10 patients. DCE-MRI confirmed falls in kinetic parameters (Ktrans/IAUGC60) in 9 of 12 patients. The change of both pharmacokinetic parameters reached a level expected to produce efficacy in one patient who had a minor response on computed tomography and a reduced serum tumor marker level. Conclusions: This is believed to be the first trial reporting the combination of radioimmunotherapy and vascular disruptive agent; each component was shown to function, and myelosuppression was dose-limiting. Optimal dose and timing of CA4P, and moderate improvements in the performance of radioimmunotherapy seem necessary for efficacy.

Introduction: Radioimmunotherapy (RIT) has been shown to be more effective against solid tumor micrometastases, possibly due to an inverse relationship between tumor size and radiolabeled antibody uptake. In this study, the accretion of radiolabeled antibody in intrahepatic micrometastases in an experimental model was investigated using quantitative digital autoradiography, enabling the analysis of antibody uptake in microscopic tumors.Methods: Mice bearing subcutaneous or intrahepatic metastatic models of LS174T colorectal cancer were injected with radiolabeled anti-carcinoembryonic antigen antibody ([I-125]A5B7). Tissues were taken to investigate distribution of radionuclide and tumor uptake. In a therapy Study, mice bearing intrahepatic metastatic tumors were injected with [I-131]A5B7.Results: Subcutaneous tumors and large metastatic deposits had similar uptake (e.g,, similar to 15%ID/g at 24 h). Small metastatic deposits had higher uptake (e.g., similar to 80%ID/g at 24 h) and prolonged retention at later time points. Small deposit uptake was significantly reduced by accompanying large deposits in the same liver. RIT resulted in increased survival time (untreated mean survival of 21.6 +/- 12.9 vs. treated mean Survival of 39.1 +/- 30.8 days), but there was a large range of response within groups, presumably due to variation in pattern and extent of tumor as observed in the biodistribution study. Liver function tests and body weight did not change with tumor growth or therapy response, strongly Supporting the use of in vivo imaging in metastatic tumor therapy studies.Conclusions: Radioimmunodetection and therapy might be greatly influenced by the size and distribution of intrahepatic tumor deposits. (C) 2009 Elsevier Inc. All rights reserved.

Renal toxicity associated with small-molecule radionuclide therapy has been shown to be dose-limiting for many clinical studies. Strategies for maximizing dose to the target tissues while sparing normal critical organs based on absorbed dose and biologic response parameters are commonly used in external-beam therapy. However, radiopharmaceuticals passing though the kidneys result in a differential dose rate to suborgan elements, presenting a significant challenge in assessing an accurate dose–response relationship that is predictive of toxicity in future patients. We have modeled the multiregional internal dosimetry of the kidneys combined with the biologic response parameters based on experience with brachytherapy and external-beam radiation therapy to provide an approach for predicting radiation toxicity to the kidneys. Methods: The multiregion kidney dosimetry model of MIRD pamphlet no. 19 has been used to calculate absorbed dose to regional structures based on preclinical and clinical data. Using the linear quadratic model for radiobiologic response, we computed regionally based surviving fractions for the kidney cortex and medulla in terms of their concentration ratios for several examples of radiopharmaceutical uptake and clearance. We used past experience to illustrate the relationship between absorbed dose and calculated biologically effective dose (BED) with radionuclide-induced nephrotoxicity. Results: Parametric analysis for the examples showed that high dose rates associated with regions of high activity concentration resulted in the greatest decrease in tissue survival. Higher dose rates from short-lived radionuclides or increased localization of radiopharmaceuticals in radiosensitive kidney subregions can potentially lead to greater whole-organ toxicity. This finding is consistent with reports of kidney toxicity associated with early peptide receptor radionuclide therapy and 166Ho-phosphonate clinical investigations. Conclusion: Radionuclide therapy dose–response data, when expressed in terms of biologically effective dose, have been found to be consistent with external-beam experience for predicting kidney toxicity. Model predictions using both the multiregion kidney and linear quadratic models may serve to guide the investigator in planning and optimizing future clinical trials of radionuclide therapy.

LB-200 Abstract LB-200 was submitted as a Late-Breaking Abstract and is embargoed until the time of presentation. The complete abstract will be posted to this site at or after the following date and time: 4/14/2008 2:30 PM.

The survival of patients with Hodgkin lymphoma (HL) has improved over recent decades due to advances in therapy and supportive care. The outcome for patients with relapsed or refractory disease, however, is still unsatisfactory. High dose therapy with stem cell support can salvage many patients but results are poor in patients with chemo-resistant, PET-positive disease pre-transplant. Novel therapies for HL have focused on monoclonal antibodies to antigens such as CD30 but these treatments have produced response rates of only 10% when given as native antibody. Radio-immunotherapy is effective treatment for a range of lymphoproliferative disorders including those that are resistant to other therapies. This phase I study utilised basiliximab, a chimeric antibody to the α-chain of the IL-2 receptor, CD25, conjugated to iodine-131 (131I) in patients with relapsed or refractory lymphomas who were resistant to or intolerant of conventional therapies and who had demonstrable CD25 expression by immunohistochemistry on tissue sections. To determine dose-limiting toxicity an accelerated titration design was used with 6 different doses employed- 370, 740, 1480, 2220 and 2960MBq/m2. Fourteen patients (9M, 5F) with a median age of 38 years (range 28–70) were treated (HL 11 patients, primary mediastinal B-cell lymphoma 1, peripheral T-cell lymphoma NOS 1, adult T-cell leukaemia/lymphoma 1). They had previously received a median of 4 therapies (range 2–8) including autologous stem cell transplant in 9 patients. Five patients were being considered for an autologous or allogeneic stem cell transplantation but had not demonstrated chemosensitivity with standard therapies. All patients were FDG-positive by PET prior to therapy. One patient had a complete response at 740MBq/m2. Six of 9 patients responded to therapy at a dose of 1200MBq/m2 or higher. There were 3 complete responses and 3 partial responses. Two of these patients who had previously not been considered for high dose therapy because of a lack of response have now proceeded to autologous or allogeneic transplant. At a clinically active dose of 1200MBq/m2 the only side effects seen were delayed myelotoxicity; the median platelet count nadir was 31x109/L(range 9–83) and was observed at a median of 38 days (range 33–53) following treatment. Neutropenia (median nadir 1.31x109/L, range 0.9–7.5) was also noted at a median of 53 days (range 37–65) following therapy. One patient was treated at a dose of 2960MBq/m2 and developed prolonged grade 4 neutropenia and thrombocytopenia requiring stem cell support. The patient died of pneumocystis carinii pneumonia. There were no other grade 3 or 4 non-haematologic toxicities noted. The 131I-labelled anti-CD25 antibody basiliximab is well tolerated at doses of 1200MBq/m2 and demonstrates clinical activity at this dose in patients who are refractory to conventional therapies. Further studies are required to determine the long term outcome of patients treated with this agent and to assess its efficacy in the pre-autograft/allograft setting.

The subtractIonmethodfor radiolmmunodetectlon(RID) of cancer is showing potentialas a diagnostictool.AnobjectIveassessmentof thistechniqueisneeded In orderto determineitsclinicalusefulness.A numericalanalysisof the RIDsclntl grams was developed and applied to 21 RIDstudies on 20 patients for whom a final diagnosishad beenestablished.The subtractiontechniquewas shownto give rise to artifactualposftlveregions,which couldbe avoidedby experiencedclinicians. When artifact-producingregionswere excluded, 97 regionswere examined (80 nontumor,17 tumor-contaIning). The “background― scintigramswere shownto be good models for nontumor regions of the antibody scintigrams, and tumor and nontumorregionswere shownto formstatisticallydistinctgroups.

PURPOSE:Antibody-directed enzyme prodrug therapy is a two-stage treatment whereby a tumor-targeted antibody-enzyme complex localizes in tumor for selective conversion of prodrug. The purpose of this study was to establish optimal variables for single administration of MFECP1, a recombinant antibody-enzyme fusion protein of an anti-carcinoembryonic antigen single-chain Fv antibody and the bacterial enzyme carboxypeptidase G2 followed by a bis-iodo phenol mustard prodrug. MFECP1 is manufactured in mannosylated form to facilitate normal tissue elimination.EXPERIMENTAL DESIGN:Pharmacokinetic, biodistribution, and tumor localization studies were used to test the hypothesis that MFECP1 localizes in tumor and clears from normal tissue via the liver. Firstly, safety of MFECP1 and a blood concentration of MFECP1 that would avoid systemic prodrug activation were tested. Secondly, dose escalation of prodrug was done. Thirdly, the dose of MFECP1 and timing of prodrug administration were optimized.RESULTS:MFECP1 was safe and well tolerated, cleared rapidly via the liver, and was less immunogenic than previously used products. Eighty-fold dose escalation from the starting dose of prodrug was carried out before dose-limiting toxicity occurred. Confirmation of the presence of enzyme in tumor and DNA interstrand cross-links indicating prodrug activation were obtained for the optimal dose and time point. A total of 28 of 31 patients was evaluable for response, the best response being a 10% reduction of tumor diameter, and 11 of 28 patients had stable disease.CONCLUSIONS:Optimal conditions for effective therapy were established. A study testing repeat treatment is currently being undertaken.

The 'magic bullet' concept predicted over a century ago that antibodies would be used to target cancer therapy. Since then initial problems that were related to specificity, purity and immungenicity of antibody-based reagents have slowly been overcome due to developments in technology and increased knowledge. As a result, antibodies are in use for many clinical applications and now comprise the second largest category of medicines in clinical development after vaccines. For antibody-based cancer therapeutics the last 20 years have met with an explosion of knowledge about the biology of the disease and potential targets as well as new technology which allows cloning and manipulation of multifunctional antibody-based molecules. However, the focus still remains on developing therapeutics that will have potential for treating cancer in people and this is efficiently assessed in mechanistic clinical trials that feed back to the laboratory for further development. This review illustrates the mechanistic approach to making new molecules for antibody imaging and therapy of cancer. It is illustrated by examples of radioimmunotherapy and antibody-directed enzyme prodrug therapy developed by the authors.

We thank Dr. Bice and colleagues for their interesting comments on our recent paper (Green et al. 1990). The writers note that the planar quantification method was used in its simplest form. They suggest that a background subtraction could have improved the accuracy of the planar estimations. While we agree that in simple phantom experiments it is trivial to subtract a constant or slowly varying background, this is of little help when dealing with actual patient scans. More complicated schemes of background subtraction often involve the prior determination of background organ size and shape using technetium 99m compounds (e. g. Eary et al. 1989). Comparison of images taken using these widely different gamma energies often suffers from differences in image size and registration. If these problems can be overcome, the problem of organ movement and geometric change must be considered. It is not possible to constrain patients to have, for example, stomach and bladder sizes constant at each scanning time over a 3week study. Eary et al. found that they could obtain good serial estimates using a "realistic human body phan tom " with constant geometry and constant organ activity ratios but, when using a more realistic live animal model, "agreement was less apparent in the two dogs which were imaged and sacrificed 48 h post infusion". We thought it sufficient to show the problems that can arise using planar imaging when background activity is present. The main part of our work was the development of a suitable method of transaxial imaging, as this is the most effective way of eliminating these problems. We agree that filtered back-projection reconstruction with dual-window scatter correction and simple attenuation correction is not a final solution to the problem if SPET reconstruction with iodine 131 is used. It is a method which is relatively simple to implement using existing gamma cameras and imaging software. We feel that the use and limitations of this technique should be evaluated as part of our immuno-directed therapy programme. The writers comment that they do not find it immediately obvious that the corrections will prove satisfactory in complex imaging situations. The results presented in our paper show that good agreement with values measured by other methods can be achieved in both phantom work and patient studies with high activities of iodine 131 by careful application of these techniques. We agree with the writers that the development of immuno-guided therapy requires accurate estimates of tumor and normal organ doses. The scheme we have presented provides a reasonably accurate basis for this quantification, which can be usefully applied while better imaging methods are being developed.