Role of radiation dosimetry in radioimmunotherapy planning and treatment dosing

Critical Reviews in Oncology/Hematology 39 (2001) 203– 218 www.elsevier.com/locate/critrevonc

Role of radiation dosimetry in radioimmunotherapy planning and treatment dosing Gerald L. DeNardo a*, Malik E. Juweid b, Christine A. White c, Gregory A. Wiseman d, Sally J. DeNardo a a

Room 3100, Hematology/Oncology, Radiodiagnosis and Therapy, Uni6ersity of California, Da6is Medical Center, 1508 Alhambra Bl6d., Sacramento, CA 95816, USA b Garden State Cancer Center, Belle6ille, NJ 07109, USA c IDEC Pharmaceuticals Corp, San Diego, CA 92121, USA d Mayo Clinic, Rochester, MN 55905, USA Accepted 12 January 2001

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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2. Purposes of radiation dosimetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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3. Methods for radiation dosimetry. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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4. Tracer vs. therapy radiation dosimetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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5. Nonmyeloablative vs. myeloablative therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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6. Marrow radiation dosimetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Traditional methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Imaging-based methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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7. Treatment dosing methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Radiation dose (cGy)-based methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Radionuclide dose (GBq)-based methods . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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8. Relationship between radiation dose and toxicity or tumor response . . . . . . . . . . . . . . .

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9. Regulatory considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract Cancer-seeking antibodies (Abs) carrying radionuclides can be powerful drugs for delivering radiotherapy to cancer. As with all

* Corresponding author. Tel.: + 916-734-3787; fax: + 916-451-2857. E-mail address: [email protected] (G.L. DeNardo). 1040-8428/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 0 4 0 - 8 4 2 8 ( 0 1 ) 0 0 1 0 9 - 3

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radiotherapy, undesired radiation dose to critical organs is the limiting factor. It has been proposed that optimization of radioimmunotherapy (RIT), that is, maximization of therapeutic efficacy and minimization of normal tissue toxicity, depends on a foreknowledge of the radiation dose distributions to be expected. The necessary data can be acquired by established tracer techniques, in individual patients, using quantitative radionuclide imaging. Object-oriented software systems for estimating internal emitter radiation doses to the tissues of individual patients (patient-specific radiation dosimetry), using computer modules, are available for RIT, as well as for other radionuclide therapies. There is general agreement that radiation dosimetry (radiation absorbed dose distribution, cGy) should be utilized to establish the safety of RIT with a specific radiolabeled Ab in the early stages (i.e. phase I or II) of drug evaluation. However, it is less well established that radiation dose should be used to determine the radionuclide dose (amount of radioactivity, GBq) to be administered to a specific patient (i.e. radiation dose-based therapy). Although treatment planning for individual patients based upon tracer radiation dosimetry is an attractive concept and opportunity, particularly for multimodality RIT with intent to cure, practical considerations may dictate simpler solutions under some circumstances. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Radioimmunotherapy; Treatment dosing; Radiation dosimetry; Radionuclide dose

1. Introduction Chemotherapy doses are determined in small cohorts of patients based on dose- escalating studies intended to determine the maximum tolerated dose (MTD) of a drug or combination of drugs. Modification of these doses for categories of patients may be implemented but there is little individualization unless conducted on an empiric basis. For some chemotherapeutic drugs, the area under the blood clearance curve (AUC) can be used to influence doses of the drug. In radiation oncology, studies conducted over several decades have shown that treatment planning for an individual patient can be used to optimize response and morbidity. Patient-specific calculations of radiation doses delivered to tumors and normal tissues are routine in external beam radiotherapy. Calibration of linear accelerators along with phantom and in vivo dosimetry help to assure the accuracy of external beam dose delivery. However, the intended radiation doses are determined by the response – morbidity relationships observed in studies of earlier patients, so that treatment planning actually represents careful definition of radiation dose distribution for each patient. Importantly, a vast body of human data that indicates a clear relationship between radiation dose and early and late normal tissue toxicity on the one hand, and between radiation dose and tumor response, even for specific tumor types, has been generated [1,2]. Radioimmunoimaging is a powerful tool that has the potential for serving as a treatment planning vehicle. Radionuclide therapy is unique because the radiolabeled drug pharmacokinetics and radiation dose distribution can be estimated for an individual patient using a tracer amount of the radiolabeled drug intended for subsequent therapy [3]. Unfortunately, radiation dosimetry for radionuclide therapies has not yet reached the sophistication of radiation dosimetry for external beam and sealed source radiotherapy. As discussed by Stabin [4], radiation dosimetry for radionuclide therapies, until recently, was determined using the concept of a standardized reference man (woman or

child). Recently, the spatial characteristics of the specific patient and energy distribution of the specific radionuclide have been used to generate patient-specific radiation dosimetry [5]. This permits radiation dosimetry to be determined for radionuclides with emissions having ranges on the order of millimeters or fractions thereof (multiple cell diameters). When dealing with radionuclides emitting alpha particles or Auger electrons, cellular, and perhaps even subcellular radiation dosimetry may be desirable. The accuracy of radionu-

Fig. 1. Comparison of mean radiation doses ( 9 S.D.) and mean therapeutic indices for tumor and body obtained in NHL patients given 67Cu-2IT-BAT-Lym-1 (n = 11, grey), 131I-Lym-1 (n =46, crosshatched) or 90Y-2IT-BAD-Lym-1 (n =13, black). Because of its more abundant and energetic beta emissions, the mean radiation dose per unit of administered radioactivity (Gy/GBq) to tumor from 90Y-2ITBAD-Lym-1 was more than twice that from 67Cu-2IT-BAT-Lym-1 which was more than twice that from 131I-Lym-1. However, the radiation dose to body from 90Y-2IT-BAD-Lym-1 was also higher than that of 67Cu-2IT-BAT-Lym-1 or 131I-Lym-1. Consequently, the therapeutic index (tumor to normal tissue radiation dose ratio) for NHL patients given 67Cu-2IT-BAT-Lym-1 (grey) was better than those for NHL patients given 131I-Lym-1 (cross-hatched) or 90Y-2ITBAD-Lym-1 (black). Although not shown, the therapeutic indices for 67 Cu-2IT-BAT-Lym-1 were generally more favorable than those for 90 Y-2IT-BAD-Lym-1 or 131I-Lym-1 for other tissues.

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clide radiation dosimetry has the potential to improve dramatically. There are many choices to be made when considering RIT both generally and for a specific patient. In addition to choice of the Ab and radionuclide to be used, the Ab and radionuclide doses must be determined. Each of these choices is significant enough to determine the success or failure of RIT. Using tracer doses of radionuclide and MIRD techniques, pharmacokinetics can be determined and radiation dosimetry estimated for a radiolabeled drug in a population of patients to assess its potential for therapy. Similarly, the pharmacokinetics and radiation dosimetry of differing radiolabeled drugs may be compared in order to evaluate their relative advantages (Fig. 1). Comparisons of pharmacokinetics and radiation dosimetrics (therapeutic indices) based on relatively safe tracer studies in small numbers of patients are of great importance when assessing differing drugs, radionuclides, or conjugation methods intended for the same purpose. Radiation dosimetry can also be estimated ‘‘after the fact’’ for the treatment dose (often using the tracer study) in order to retrospectively assess the relationships between estimated radiation dose distribution and efficacy or toxicity. There seems little doubt that radiation dosimetry is required in phase I dose-finding studies, and probably also in phase II studies to reinforce the validity of the

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limited phase I data and to afford retrospective toxicity/efficacy comparisons even if the final treatment dosing is based on other methods. Radiation dosimetry in phase I, II studies permits acute and late toxicities to be related to the radiation dose delivered to the normal tissues and predictive risks to be determined for various treatment plans. In the same manner, tumor response can be predicted on the basis of the estimated tumor radiation dose. Treatment planning strategies that provide recommendations for treatment of individual patients based upon accurate estimates of radiation dose distribution for each combination of radionuclide and targeting Ab have been developed (Fig. 2) [6– 9]. An integrated radionuclide treatment planning and radiation dose estimation system, although designed for RIT, can be used generally in radionuclide therapy to provide standard phantom or patient-specific radiation dose estimates.

2. Purposes of radiation dosimetry Early RIT trials were mostly pragmatic, without detailed treatment planning or pretreatment estimates of anticipated radiation doses to the cancer or other tissues. In most instances, radioimmunoimaging was used to demonstrate uptake of radionuclide in the cancer (Table 1).

Fig. 2. Treatment planning system using kinetic models. A kinetic model combined with a parameter estimator is applied to patient data to obtain distribution and cumulated activity estimates. These estimates are then used as input to a therapy planner which produces a radiation dose-based plan for RIT for each patient. The process is iterated, if necessary, to complete the therapy regimen. (ECT-radionuclide SPECT or PET; TCT-X-ray CT or MRI) (Reproduced with permission from Int. J. Radiation Oncology Biol. Phys. 11:335 – 348, 1985.)

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Table 1 Radioimmunoimaging in radioimmunotherapy

Table 3 Image elements required for pharmacokinetics (cumulated activity)a

Presence of specific tumor targeting (efficacy) Absence of specific normal tissue targeting, or quantitation of amount (safety, toxicity) Quantitation of radiation absorbed doses for the tumor and the normal tissues (e.g. dose-limiting tissues) (safety, toxicity, efficacy, treatment planning)

Sequential quantitation of radioactivity in the patient using nuclear imaging Definition of regions of interest (ROI) on image Adjustment of ROI counts for geometry Adjustment of ROI counts for attenuation Adjustment of ROI counts for coincidence (therapy dose) Conversion of total tissue counts to counts per unit mass (volume) using CT, MRI, radionuclide image or MIRD reference man (woman or child) Comparison with reference standard from administered radiolabeled Ab Provides activity per unit mass for each defined tissue and image, and cumulated activity for each defined tissue on the sequence of images

A primary purpose for obtaining radiation dosimetry is to maximize the likelihood for a safe and optimally effective treatment for each patient (Table 2) [6]. The ultimate purpose of radiation dosimetry is somewhat controversial at this time, and may depend on the treatment goals. Certain situations may require treatment planning for an individual patient whereas others may not. Radiation dosimetry can nearly always be utilized as a tool for assessing results or as a guide to establish the safety of RIT with a specific radiolabeled Ab in the early stages (i.e. phase I or II) of drug evaluation.

3. Methods for radiation dosimetry External planar imaging with a gamma camera has traditionally been used to measure radioactivity. Single photon emission computed tomography (SPECT) [10] and positron emission tomography (PET) [11] represent attractive, but less established, methods for quantifying radiolabeled Ab pharmacokinetics. Computed tomogTable 2 Purposes of radiation dosimetry for targeted therapy Determine the druga amount (mass) required for optimal targeting Characterize the pharmacokinetics and radiation dosimetry of a drug Compare the pharmacokinetics and radiation dosimetry of competing drugs or radionuclides Identify the likely critical (dose-limiting) tissue(s) for radiotherapy Provide the basis for radionuclide dose-escalation in a phase I therapy trial Reflect the variability of the drug’s pharmacokinetics and radiation dosimetry in phase I, II therapy trials Prospectively or retrospectively serve as the basis for comparisons of toxicity and efficacy with radiation doses to normal tissues and tumors, respectively Provide information upon which to improve the drug or conditions of giving the drug or therapy program Provide information upon which to implement combinations of therapy, e.g. optimal sequence and timing of drugs, timing of marrow cell reinfusion, pharmacokinetic interactions of drugs, etc Provide information upon which to direct treatment planning for the individual patient or groups of patients a Drug is used as a generalization for radiolabeled agents, such as Abs and peptides.

a

Additionally, sequential blood and excrement samples should be quantitated.

raphy (CT) and magnetic resonance imaging (MRI) can be used to define tumor volumes accurately [12,13]. To develop a RIT treatment plan for individual patients, one must be able to estimate radiation dose [14]. Radiation dose is usually estimated, because its direct measurement in vivo is not practical. Radiation dose estimates may be used to decide whether a patient should begin therapy and to prescribe the radionuclide dose (amount of radioactivity) to be administered. The unique physiological characteristics of each patient limit the possibility of accurately predicting the radiolabeled drug pharmacokinetics and thus radiation dose, before injection of the radiolabeled drug. The pharmacokinetic information required to estimate the radiation dose can be obtained using a tracer quantity of radiolabeled drug pretherapy (Table 3). The mass of drug should be similar to the anticipated therapy amount or documented not to alter the pharmacokinetics. The validity of tracer radionuclide doses in predicting the kinetics of treatment radionuclide doses has been documented [15– 20]. Imaging is performed at multiple times to determine the quantitative spatial distribution of the radionuclide (Fig. 3). Correction methods are required to make the response of the gamma camera independent of its sensitivity for the radionuclide, the depth of the radionuclide in the patient and the body shape and composition. The cumulated activities (residence times) for radionuclide in tumors and in other tissues are estimated by linking the serial quantitative images. This process provides the cumulated activity (area under the curve, AUC, after radionuclide decay), that is, the amount of radioactivity integrated over time (Fig. 4). Pharmacokinetic data are integrated using one of several representations for the observed data to obtain cumulated activities (residence times): (1) direct integration; (2) least squares analysis; or, (3) compartmental modeling. Cumulated activity, and the volume or mass of tissue in which it is distributed, is the principal

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Table 4 Radionuclide physical elements (constants) required to convert cumulated activities to radiation absorbed doses Nature of the radiations from the radionuclide and their tissue absorption characteristics (S values) Specify the defined target tissue, its cumulated activity and S value to obtain source to source radiationa Specify the defined target tissue and other major radiation source tissues, their individual cumulated activities and S values to obtain additional major sources to target tissue radiation Specify the defined target tissue and all other radiation source tissues (remaining body) cumulated activity and average S value to account for remaining contributions from less significant sources to target tissue radiation a

This is the major contributor to radiation dose for most therapeutic radionuclides on drugs that localize in tissues.

Fig. 3. Anterior planar image of chest and upper abdomen of patient soon after administration of radiolabeled Ab. Liver and background region of interest used to quantitate radioactivity is illustrated. Identical quantitations on serial images are used to obtain cumulated activity.

quantity required for radiation dosimetric calculations [21]. One object-oriented system designed by Liu et al. [22] is based on modules including functions for image processing, quantitative activity calculations, modeling of radioactivity over time curves and radiation dose calculations (Table 4). The only required user inputs are definition of tissue regions of interest (ROIs), urine and blood radioactivity, and patient demographic data. In this system, two methods are available for radiation dose estimation (fraction of the energy that is absorbed in a tissue) given the cumulated activities (residence

times): (1) the first is based on the standard Medical Internal Radiation Dose (MIRD) phantom for a standardized man, woman or child [23]; and (2) the second uses the Monte Carlo-assisted voxel source kernal algorithm with the provision of the relevant S values to provide a patient-specific tissue radiation dose estimate based on actual geometric relationships for that patient [24]. The calculation of radiation (absorbed) dose to tissue represents the conversion of radioactivity into energy emitted and absorbed per unit mass (Table 4). Thus, traditional MIRD equations involve both a biological and a physical component. There is greater uncertainty regarding the biological than the physical component of the MIRD equation. Although radiation dosimetry estimates for radionuclide therapy are not yet highly accurate, they have been shown to be reproducible in individual patients over time [25] when performed by experienced individuals, so that they can be relied upon for predictive and comparative purposes.

4. Tracer vs. therapy radiation dosimetry

Fig. 4. Tissue radioactivity curves adjusted for radionuclide decay. Comparison of the relative uptake in tumors, body, blood and potential critical tissues in this patient given 131I-Lym-1 Ab must correct for the relative size (mass) of each tissue.

Radionuclide therapy is unique because the radiation dose distribution can be estimated for an individual patient using a tracer amount of the radiolabeled drug intended for the subsequent therapy [6,26,27]. If the pharmacokinetics are the same for tracer and therapy doses of radionuclide, tracer studies can be very useful to predict radiation doses from therapy [6]. Tracer pharmacokinetic studies are often used in treatment planning for radionuclide therapy, including RIT. Maxon et al. [28] found that a pretreatment tracer study with 131I-iodide provided a reliable indicator of whole-body retention of 131I after therapy for thyroid cancer. Successful thyroid ablation with 131I-iodide correlated with radiation dose, but not with the amount of administered 131I; response of metastases also correlated with their radiation dose. Tracer studies have been used to predict therapeutic doses for radiolabeled Abs

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[16,28,29]. Good correlations have been reported for tracer and therapy pharmacokinetics and radiation dosimetry for Abs [15– 20,30,31]. The predictive value is dependent upon the masses of Ab administered for tracer and therapy doses, the interval between doses, and the biologic conditions for both studies (e.g. absence of human antimouse Abs or interfering drugs) [17]. Contrarily, extrapolation from a general population to an individual patient is tenuous because radiation doses depend on pharmacokinetics which are patient-specific. For example, radiation dose to normal marrow cells incident to targeting of radiolabeled Ab on malignant cells in the marrow is unique for each patient [32]. Press et al. [31,33] first used tracer radiation dosimetry for individual patients to determine the treatment dose of 131I-anti-CD20 Ab for each NHL patient based on defined radiation dose limits for lung, liver and kidney, potentially dose-limiting organs, for myeloablative dose-escalating phase I and constant radionuclide dose phase II RIT trials. Richman et al. [34] and Juweid et al. [35,36] used this approach for myeloablative RIT for breast cancer using 131I labeled Abs and medullary carcinoma using 131I and 111In/90Y labeled Abs, respectively. Kaminski et al. [37] have done so for non-myeloablative RIT for NHL. Although 90Y has attractive properties for therapy, its secondary bremsstrahlung is less suitable for imaging in patients, so that a chemical analogue of 90Y, 111In, is often used as a surrogate for imaging to obtain pharmacokinetic data from which to calculate radiation dosimetry for 90Y RIT. Using newer chelators, 111In and 90Y labeled Abs have similar pharmacokinetic behavior thereby justifying the use of 111In as a surrogate to calculate radiation dosimetry for 90Y RIT [19,29,38]. However, not all chelators can be assumed to bind both indium and yttrium stably. Another example of different radionuclides for tracer and therapy has been the use of 99mTc labeled Ab as a tracer to predict dosimetry for 186Re labeled Ab in patients. Breitz et al. [39] used 99mTc labeled NR-CO-02 (Fab’)2 as a tracer to predict dosimetry for 186Re labeled NR-CO-02. 186Re dosimetry could not be reliably predicted for individual patients, perhaps due to the different Ab masses that were administered for the two studies, and/or the difference in the physical half-lives of these radionuclides. If a radionuclide with a short physical half-life is used to predict radiation dosimetry for a radionuclide with a substantially longer half-life, potentially important pharmacokinetic data for later time points will be missed. This may result in an unreliable time-activity curve, and, hence, unreliable radiation dosimetry. In summary, tracer radiation dosimetry predicts therapy dosimetry in principle, and often in practice for individual patients, but the relationship between tracer and therapy studies must be documented for each system and set of conditions.

5. Nonmyeloablative vs. myeloablative therapy The efficacy of drugs intended for the treatment of malignancies is determined by the relationship between the drug’s effect on the malignant tissue and its effect on normal tissues. In practice, normal tissue tolerance limits the amount of the drug that can be administered. Although there have been exceptions, the dose-limiting (critical) normal tissue for RIT, and for many chemotherapeutic drugs has been the bone marrow in the absence of strategies such as bone marrow reconstitution (marrow and/or peripheral stem cell transplantation). Myelotoxicity manifested by peripheral blood cell cytopenias has been dose-limiting in most clinical trials of RIT. Thrombocytopenia and leukopenia/neutropenia have usually been the initial and most severe manifestation of this toxicity. Myelotoxicity can be assessed directly (albeit with large sampling errors) using examination of the bone marrow biopsy and indirectly using peripheral blood counts. Although myelotoxicity has generally been dose-limiting in trials of RIT, the degree of myelotoxicity has varied among patients given similar amounts of radionuclide, and from one therapy dose to another in the same patient [40–51]. There is an increased likelihood of advanced myelotoxicity if the patient has peripheral blood cell abnormalities before RIT [52] or the marrow is compromised by prior therapy [43]. Larger doses of radionuclide can be given to selected patients because they have relatively normal peripheral blood cell counts and normocellular bone marrows uninvolved by the malignancy. Treatment programs (and protocols) for RIT should incorporate these factors into the decision process. Press et al. [53,54] were the first to use high-dose RIT as a substitute for chemotherapy with bone marrow reconstitution in patients with non-Hodgkin’s lymphoma (NHL). Treatment was designed using tracer radiation dosimetry to determine the prescribed radionuclide dose that would deliver no more than the defined MTD to dose-limiting normal tissues (lung, liver, kidney) in each patient. Patient cohorts, treated at progressively higher normal tissue radiation doses, were used to determine the MTD to the most sensitive normal tissue, excluding marrow. The MTD for the lung, the dose-limiting tissue, was determined to be 2700 cGy from a single radionuclide (131I) dose [31]. Interestingly, this radiation dose is 35% higher than the lung tolerated dose of 2000 cGy for 5% complications within 5 years (TD5/5) when using fractionated external beam radiation, suggesting that the effects of radiation from RIT and from fractionated external beam, at least in the case of the lung, are somewhat different. The remarkable success of this approach prompted others to implement radiation dose-based designs, either using red marrow or total body radiation doses for non-

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myeloablative RIT or ‘‘critical organ’’, typically lung, liver and kidney, radiation doses for myeloablative RIT for dose-escalation and radionuclide dose selection [29,34,35,47,55] and subsequent constant dose trials. Although marrow is commonly dose-limiting for non-myeloablative, and lung for myeloablative, RIT, this must not be assumed to apply to all circumstances. Juweid et al. [35] observed grades 1– 3 gastrointestinal symptoms in medullary thyroid cancer patients after 131 I-MN-14 F(ab)2 followed by bone marrow reconstitution. When high doses of 90Y labeled NR-LU 10, another anti-adenocarcinoma Ab, were administered, gastrointestinal symptoms of sufficient significance to necessitate a reappraisal of the conventional MIRD model for calculating gastrointestinal tract radiation dosimetry were observed [56]. In that case, there was immunohistologic evidence for binding of the Ab to gastrointestinal epithelial cells due to expressed antigen. Clearly, detailed radiation dosimetry (and pharmacokinetics) is essential for phase I Ab studies in order to assure patient safety at this and later stages of drug development as well as to facilitate drug development. In a review article, Stabin [4] points out the progress that is being made toward improving marrow radiation dosimetry and its importance for radionuclide therapy. As bone marrow reconstitution has become incorporated into radionuclide therapy, radiation dosimetry for other organs will require corresponding attention.

6. Marrow radiation dosimetry More than 200 cGy acute total body, high dose rate radiation is required before significant myelotoxicity occurs in otherwise healthy humans [57]. Benua et al. [58] have observed that 200– 400 cGy to the marrow was the dose limit for 131I-iodide therapy in patients with thyroid cancer. These patients do not usually have preexisting, compromised bone marrows, nor does thyroid cancer extensively involve the marrow. A substantially lesser radiation dose to the marrow from 131 I-labeled Abs has been reported to produce myelotoxicity (grade 3 or higher) in patients [40– 43,47– 51,59,60]. Because bone marrow is the major critical organ in nonmyeloablative RIT, improved methods for calculating marrow radiation doses have been developed [61–69]. Nevertheless, these models do not always provide marrow radiation doses that correspond with the observed degree of myelotoxicity, likely due to a heterogeneous, heavily treated patient population and varying degrees of marrow involvement by tumor resulting in targeting of the marrow [32,52,70]. For radiation dose to the bone marrow to be meaningful, all sources of radiation must be considered. The marrow can be irradiated because of the nonspecific presence of radiolabeled Ab in its extracellular fluid,

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often referred to as blood compartment or contribution, and in the general tissues of the body, referred to as body contribution (Table 5). Specific uptake of radionuclide in skeletal or marrow elements because of specific Ab or radionuclide targeting to normal marrow/bone elements represents a potential source of irradiation to the bone marrow when using certain radiolabeled Abs. The advent of more stable chelating agents for radiometals, like 90Y, has substantially reduced the problem of ‘leakage’ of radionuclide to the bone (or marrow). Many malignancies, particularly those of the hematopoietic system, breast, and prostate, involve the marrow and skeleton so that specific targeting of the malignancy involves potential ‘spillover’ of radiation to normal marrow cells from radionuclide emissions with long range.

6.1. Traditional methods Methods for determining the radiation dose delivered to bone marrow have traditionally addressed contributions from radionuclidic sources in blood, body or both [62,64,65]. As a result of studies sponsored by the Dosimetry Task Group of the American Association of Physicists in Medicine, Siegel et al. [65] proposed a standardization of the blood method for marrow radiation dose. The red marrow radiation dose determined, using this method, is based on a first order approximation of marrow-to-blood activity concentration ratio of 0.2–0.4 [32,47–49,52,66]. According to the recommendations of the Dosimetry Task Group, blood-derived estimates for marrow radiation dose from radiolabeled Abs are valid only if the marrow is devoid of specific uptake due to targeting of normal or abnormal (malignant) marrow elements. Sgouros et al. [66] proposed modifications to account for the effect of hematocrit on the relationship of marrow activity to that of blood. These methods for estimating marrow radiation dose require that, in addition to the red marrow self-dose derived from blood, the remainder-of-body radiation dose be taken into account to arrive at the final red Table 5 Sources of radiation to bone marrow from treatment with radiolabeled antibodies Nonspecific sources: common to all radiolabeled Abs Nonpenetrating emissions from radionuclide distributed in the extracellular fluid of marrow Penetrating emissions from radionuclide in the remaining tissues Specific marrow/bone targeting: unique to the patient, malignancy, marrow/bone region, and radiolabeled Ab Radiolabeled Ab targeting of normal marrow/bone elements; escape of radionuclide and incorporation in marrow/bone elements, e.g. 90Y in bone. Marrow/bone malignant cells: ‘‘spillover’’ from radiolabeled Ab binding to the marrow/bone malignancy

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6.2. Imaging-based methods

Fig. 5. Illustrative case with extensive NHL in the bone marrow. Posterior planar lumbar vertebral image from posterior view shows 131 I-Lym-1 targeting of bone marrow at 6 h. Marrow NHL was confirmed by bone marrow biopsy. Significant myelotoxicity occurred after a single small dose (2.2 GBq) of 131I-Lym-1. (Cancer Vol. 73, No. 3, 1994,1038 – 1048. Copyright© 1994 American Cancer Society. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)

marrow radiation dose. The contribution of the remainder-of-body dose is particularly important for radionuclides like 131I, that have an abundance of photon (X-ray-like) emissions that can contribute as much as 50% of the total marrow radiation dose [71]. Recently, there have been efforts to correlate the radiation doses to marrow estimated by these methods with subsequent evidence for myelotoxicity [52,63,68]. Although positive correlations have been reported, they have been less than definitive, presumably because of confounding factors, such as prior chemotherapy and effects of the malignancy itself. Tardivon et al. [72] has shown that MRI reveals NHL in the marrow even when marrow biopsies are negative. Radiation dose to the marrow from radionuclide targeted to malignant cells in the marrow and skeleton is evaluable (Fig. 5) [32]. Several groups have described imaging methods for measuring the marrow radiation from targeted radionuclide [61,67–69]. Radiation dose estimated from images of the lumbar vertebral marrow (targeted marrow radiation) correlated better than the correlations for blood, body, or blood and body for all blood cell parameters studied in patients with NHL [63]. As expected, the correlation of radiation dose with thrombocytopenia was best. These observations are consistent with those of Juweid et al. [73] for patients with NHL.

Although the radiation from specific targeting of radiolabeled Abs is primarily absorbed by the malignant cells, there can be a substantial, albeit variable, contribution to the adjacent normal marrow elements. In patients, such as those with NHL, likely to have marrow targeting, prediction of myelotoxicity by conventional blood and body contributions to marrow is substantially improved by the use of radiation dose to marrow estimated from images. In the experience of DeNardo et al. [32] with 131I-Lym-1 in B-cell malignancies, the contribution to myelotoxicity from targeting of marrow malignancy has clearly been important. Estimations of radiation dose to the bone marrow from 131I circulating in the blood and body of the patient did not account for this contribution. Specific marrow targeting was believed to be a major factor in the observed variability of myelotoxicity in the patients. Imaging of the distribution of the radiolabeled Ab provides useful clues (Fig. 5), and quantitative imaging methods have been described for estimating the radiation contribution to marrow from targeting of malignant (or normal) tissues in the marrow (or bone) [61,63,68,74]. Marrow targeting can contribute marrow radiation that is several times greater than that from the blood and body of the patient [61,63,73,74]. Increased toxicity of 90Y-labeled antibodies because of 90Y escape from the immunoconjugate and subsequent uptake and prolonged retention by bone has been observed to increase myelotoxicity in experimental [75–77] and clinical [78,79] studies. As stated earlier, this problem has been greatly reduced by the use of more stable chelates for 90Y.

7. Treatment dosing methods A variety of methods are available for selecting a treatment dose for RIT (Table 6). The following sections address these methods including radiation dosebased methods and radionuclide dose-based methods. No attempt has been made to address the important Table 6 Radioimmunotherapy dosing methods Radiation dose (cGy)-based methods Marrow radiation dose (nonmyeloablative) Total body surrogate Blood/body surrogate Marrow imaging Critical (dose-limiting) organ radiation (myeloablative) Radionuclide dose (radioactivity, GBq or mCi) - based Methods Fixed total GBq (mCi) GBq (mCi) per unit body weight (kg) GBq (mCi) per unit body surface area (m2)

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issue of single vs. multiple (fractionated) dose RIT in this publication.

7.1. Radiation dose (cGy) -based methods Radiation dosimetry to major normal tissues and tumors has been considered in radionuclide therapy since the mid-1940s when radioiodine therapy was demonstrated to be effective for functioning thyroid cancer metastases [80,81]. Since the mid-1980s, interest in radiation dosimetry treatment planning systems for RIT has increased [6,9,13,22,82– 84]. Although this concept was endorsed by many, radionuclide activitybased dosing was used almost universally in earlier trials. Press et al. [31,53,54] were the first to use highdose RIT with bone marrow reconstitution. In these trials, the administered radionuclide dose and dose escalation were determined based on maximum radiation doses to dose-limiting tissues. The success of this approach prompted others to explore similar designs, either using marrow or total body radiation dose for non-myeloablative RIT and critical organ (lung, liver, kidney) radiation doses for myeloablative RIT [29,34,35,47,55]. The use of the total body radiation dose as a surrogate for the red marrow radiation dose has been proposed for 131I-labeled Abs [55]. Theoretically, this approach can be justified if there is a good correlation between the total body radiation dose and the red marrow radiation dose determined by blood, or if the remainder-of-body dose contributes greatly to the marrow dose, and if marrow radiation dose from targeting is not significant. An example of systematic utilization of the total body radiation dose as a surrogate for the marrow radiation dose is the approach used to determine the radionuclide dose of 131I-B1 anti-CD20 Ab (Bexxar™; Coulter Pharmaceuticals, Inc., Palo Alto, CA) for patient-specific treatment of patients with NHL [55]. The dose-limiting toxicity for this Ab has been 75 cGy radiation to the total body in patients who had less than 25% marrow NHL; this total body MTD is similar to that reported for other 131I-Abs [47–51]. Based on data from trials of 131I-B1 anti-CD20, total body radiation dose, simply obtained for individual patients, can be used to determine the radionuclide dose (GBq) to be prescribed for each patient. Each patient’s whole body residence time (cumulated activity) is estimated from three whole body radioactivity measurements obtained over about a week, using either a thyroid probe system or a whole body gamma camera. The residence time, in conjunction with the patient’s weight, determines the desired amount of radionuclide for the subsequent therapeutic dose. Dose attenuations are instituted for obesity and reduced blood platelet counts. The simplicity of the approach, coupled with its ease of use, make it attractive as a

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clinically realistic method for prospectively determining the radionuclide dose (GBq) for individualized treatment of patients with NHL. Some of the patients have had total body residence times three times longer than others. Thus, it was reasonable to adjust the radionuclide dose to reflect individual-specific biologic clearance of the radiolabeled Ab on a patient-to-patient basis. This enabled patients to receive larger tumor radiation doses (cGy), while not exceeding the maximum tolerated dose, than if a single maximum tolerated dose (GBq) were given. Importantly, the duration of response for patients with a complete remission was significantly longer in the group that received the higher total body dose of radiation (65– 85 vs. 25–55 cGy), thereby supporting the importance of the higher radiation dose. To deliver these higher doses, individualization of the administered radionuclide doses (GBq) was essential [85]. Although this approach can be considered for other 131I-labeled Abs [71], its validity for Abs labeled with a residualizing, non-penetrating radionuclide, such as 90Y, is questionable.

7.2. Radionuclide dose (GBq) -based methods Radiation dosimetry was performed in early RIT trials, but treatment dosing was often based on the amount of administered radionuclide in terms of total activity (GBq), activity per unit of body weight (GBq/ kg), or activity per unit of body surface area (GBq/m2). This radionuclide dose-based approach was prevalent because of its convenience and the uncertain relationship between radiation dose from radiolabeled Abs and toxicity. Radiation dosimetry for these trials, based on standard man assumptions, served as a basis for demonstrating radiation dose-response relationships. As expected, a number of these RIT trials that involved 131 I-labeled Abs demonstrated that response and toxicity correlate better with estimated radiation dose than with administered radionuclide activity. Dosimetric methods provide a meaningful description of the biodistribution of the radiolabeled Abs and can be used to establish a database of estimated radiation doses to tumors and normal organs. Radiation dosimetry data obtained in early trials of a radiolabeled Ab are useful for determining safe and effective radionuclide doses for phase II studies. Dosimetry can also be useful for determining individual patient doses to account for significant variability in pharmacokinetics, and the time period for patient isolation or hospitalization, for 131I-labeled Abs. Disadvantages of radiation dosimetry include complexity, cost, patient inconvenience, and inherent sources of error (i.e. region of interest delineation) leading to inaccuracy and making it challenging to adopt universally across institutions. With supportive clinical data demonstrating that standard doses of radiolabeled Abs have acceptable

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safety and efficacy profiles, and that variability in excretory clearance is not significant, radiation dosimetry may be eliminated for defined patient populations allowing greater numbers of patients to be treated in a more cost-effective, out-patient setting. An example of treatment that does not involve radiation dosimetry in all patients is RIT using IDEC-Y2B8 (Zevalin™, IDEC Pharmaceuticals Corp., San Diego, CA), a 90Y labeled anti-CD20 Ab. With this radiolabeled drug, remarkable tumor responses and response rates have been achieved in association with acceptable toxicity in patients with less than 25% marrow NHL. Radiation dosimetry has been performed on 179 patients treated with IDEC-Y2B8 [86,87]. In an analyses of all 179 patients, no correlation could be demonstrated between estimated red marrow radiation dose and hematologic toxicity [86] though hematologic toxicity was related to clinical parameters such as bone marrow reserve, as reflected in baseline platelet counts, and bone marrow NHL. Other radiation dosimetry and pharmacokinetic parameters could not predict hematologic toxicity including total body radiation dose, blood half-life, blood AUC, plasma half-life, and plasma AUC. Treatment with IDEC-Y2B8 in more than 250 patients, including treatment without radiation dosimetry, has been associated with an acceptable safety profile [88–92]. Toxicity has been primarily hematologic, transient, and reversible. Red marrow radiation dose has been estimated from blood activity data or sacral image data after administration of 111In labeled Zevalin using the MIRDOSE3 personal computer software. All 179 patients for whom radiation dosimetry has been performed have met protocol-defined acceptable limits of less than 300 cGy to bone marrow [92]. One potential explanation for the lack of correlation between dosimetric or pharmacokinetic parameters and hematologic toxicity is the inherent variability in bone marrow reserve for this group of relapsed NHL patients. The number of prior treatment regimens varied from one to nine. Neither blood-derived nor sacral image-derived bone marrow radiation dosimetry accounts for decreased bone marrow reserve and increased toxicity seen in patients where bone marrow has been damaged by prior chemotherapy and external beam radiation. A blood-derived red marrow radiation dosimetry method is acceptable for evaluation of estimated red marrow radiation dose when RIT is used in diseases that do not localize to bone marrow. However, bloodderived red marrow radiation dosimetry does not account for specific Ab targeting of the marrow due to involvement with NHL. Interpatient variability in bone marrow involvement with NHL results in variable specific targeting of active bone marrow. For these patients, image-based marrow radiation dosimetry may be

preferred. Unfortunately image-based radiation dosimetry has other shortcomings as bone marrow radiation dose is sometimes under or overestimated due to the difficulty in separating sacral regions from nearby adenopathy and non-uniformity of malignant involvement of the marrow. Juweid et al. [73] reported similar obstacles using sacral imaging techniques to estimate red marrow radiation dose from the radiolabeled antiCD22 Ab. In contrast to dosimetric and pharmacokinetic parameters, Witzig et al. [92] showed that hematologic toxicity correlated well with clinical factors including baseline platelet count and percent bone marrow involvement with NHL in phase I/II studies of IDECY2B8. Based on these data, subsequent studies of IDEC-Y2B8 are now performed without radiation dosimetry provided that the patient population meets the eligibility criteria of less than 25% bone marrow involvement with lymphoma by biopsy, greater than 100 000/mm3 platelets at baseline, and no prior bone marrow reconstitution procedure. Administered radionuclide doses for patients are calculated on megabecquerels of 90Y per kg of body weight with 14.8 MBq/kg (0.4 mCi/kg) as the standard dose and 11.1 MBq/kg (0.3 mCi/kg) as the reduced dose for mild thrombocytopenia.

8. Relationship between radiation dose and toxicity or tumor response A radiation dose to tissue response relationship has been established for conventional radiotherapy. The relationship between radiation dose and tissue cytotoxicity is based on studies as diverse as designed studies in cell culture and animal models, accidental radiation events, radiation incident to warfare and military testing, epidemiologic studies of natural radiation, and radiation intended for therapeutic purposes. The relationship between early and late normal tissue toxicities, and tumor response for external beam and sealed radionuclide source radiotherapy is very well documented and is a fundamental dogma for conventional radiotherapy [1,2]. This relationship between cytotoxicity and radiation dose from radionuclide therapies, such as RIT, has been valid for organs such as liver, lung and kidney, and would be expected to be valid for bone marrow in patients without significant prior bone marrow damage from therapy. In extensive preclinical RIT studies in mouse tumor models, a strong correlation between radiation doses to normal tissues or tumor and toxicity or tumor response has usually been observed [93–97]. Despite excellent preclinical evidence, early RIT clinical trials showed an absent or rather weak relationship between radiation dose (and radionuclide dose) and

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toxicity or tumor response [83,98,99]. As stated earlier, trials thus far have been conducted in heterogeneous patient populations with advanced disease. However, Wong et al. [100] have recently provided one the strongest radiation dose-response relationships observed for RIT. They reported a linear correlation between increases in chromosomal translocations in lymphocytes, an established biologic parameter (in situ biodosimeter) for radiation, for marrow radiation dose, whole body radiation dose and administered radionuclide activity in patients with metastatic CEA-producing malignancies given 90Y labeled for RIT. In an instance where RIT using 131I-B1 anti-CD20 Ab was used as initial front-line therapy for NHL, hematologic toxicity correlated much better with radiation dose than when the same system was used after chemotherapy relapse [101]. In addition, the first clinical evidence for a strong relationship between tumor response and tumor radiation dose from RIT has recently been reported [102]. Improved methods for accounting for all sources of radiation to dose-limiting tissues may explain increasing numbers of RIT clinical trial reports demonstrating a correlation between radiation dosimetry data and toxicity. For example, the correlation between red marrow radiation dose and hematologic toxicity was improved when contributions from radiolabeled Ab targeting of marrow NHL (imaging) was considered rather than only distribution of radiolabeled Ab in extracellular fluid [63,73]. Liu et al. [103] have shown a relationship between radiation doses to the lung and pulmonary toxicities in a myeloablative RIT program. Others have similarly shown good correlations for dose-limiting organs in myeloablative RIT [34,36]. Finally, it should be pointed out that radiation dosimetry is in evolution. Only recently, has patient-specific dosimetry, as opposed to standard man methods, been implemented to any degree, so that there is reason to believe that correlations may improve in the future.

9. Regulatory considerations Although it may be premature for the medical and scientific community, and certainly for regulatory agencies, to adopt a common dosing method for RIT for all radiolabeled Abs and malignancies, the authors agree upon the importance of establishing complete radiation dosimetry for each system in phase I trials at the least, and most probably also in phase II trials, for the following reasons. Safety is highly dependent upon early detection of unexpected biodistributions and pharmacokinetic behavior for each radiolabeled Ab (and quite likely for each Ab) in a small number of patients. It is also necessary to establish tumor targeting and its degree at this same stage. Additionally, the

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relationship between radiation dose and toxicity/efficacy must be established so that a clear decision to proceed or to terminate the trial is based upon known safety considerations and projections of the likely toxicity/efficacy relationships to be expected in subsequent trials. Although radiation dosimetry should be an integral part of phase I trials at the least, this does not imply that a radiation dose-based method is the only method to be used in these or later trials, or in subsequent routine practice for an approved application. During the developmental phase of a drug and therapeutic approach, flexibility in choice of dosing method is of paramount importance and appropriately reflects the uncertain state of affairs. Considerable interest has recently been shown in new designs for phase I clinical trials. Because too many cancer patients in phase l clinical trials are treated at doses of drugs well below biologically active levels, giving little chance of response, a study of new designs for phase I and II trials was recently published [104]. This study suggests that pharmacokinetic differences are an important source of interpatient variability and states that ‘‘In such cases it may be advisable to attempt to control systemic exposure rather than (administered) dose.’’ In RIT protocols driven by radionuclide doses, many patients may be treated well below the biologically active level, minimizing the opportunity for antitumor response, and providing data difficult to interpret in terms of radiation dose distribution, acute toxicity, cumulative toxicity, and MTD. These protocol designs may require more patients and dollars than do radiation dose-driven protocols, while providing little useful information about the variability among patients relative to the normal tissue radiation dose that can be tolerated without dose-limiting toxicity. If a high dose of radiation can be delivered to a tumor, there is a good chance of eradicating the tumor and possibly curing the patient. On the other hand, such a dose may pose a substantial risk to the patient’s normal tissues. This fact has required some patients to be treated with less radiation than ideal and made it difficult to optimally treat patients. Although this problem is not unique to RIT, but is also common to chemotherapy, some believe that the feasibility of radiation dose-driven protocols for RIT should be exploited to maximize the risk-benefit relationship. Kaplan et al. [105] have shown for Hodgkin’s disease that rigorous radiation-dose-distribution-driven external beam radiotherapy permitted delivery of higher radiation doses to tumors and converted palliation to cure of many patients. However, simplifying the conduct of RIT trials should also be a primary concern, particularly if this modality is to become part of the standard management of cancer. As long as simple radionuclide-driven treatment methods prove, in practice, to be both safe

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and effective, they should be recognized as valid, reasonable, and possibly, preferable. In order to determine if the radiation dosimetry – driven method is indeed superior to the radionuclide-driven method, one has to clearly demonstrate that the frequency of excess toxicities and/or tumor underdosing are significantly lower with the former than with the latter method when treating at the MTD with each approach. Demonstrating a substantially lower variability in toxicity (i.e. more predictable toxicity) with the radiation dosimetry, as compared with the radionuclide-driven, method may not be as critical but would also strengthen the argument for choosing the former method. Investigations should be initiated to address these issues, preferably in the context of therapy studies utilizing the same Ab labeled with the same radionuclide in similar groups of patients (ideally in randomized trials), for both nonmyeloablative and myeloablative RIT with assessment of both hematologic and non-hematologic toxicities.

Acknowledgements We wish to thank the many medical physicists with whom we have worked, and from whom we have learned. They should not be held responsible for our shortcomings and conclusions. Additionally, we wish to thank Bryan R. Leigh, MD (IDEC Pharmaceuticals, Corp., San Diego, CA) and Lawrence E. Williams, PhD (City of Hope National Medical Center, Duarte, CA) for helpful input during preparation of the manuscript.

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Biographies Dr Gerald Denardo is Professor Emeritus of Internal Medicine, Radiology (Nuclear Medicine) and Pathology in the Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis School of Medicine, in Sacramento, California, USA. His interests lie in the development of new therapeutics for lymphoma, breast and prostate cancer using radioisotope conjugated monoclonal antibodies, genetically engineered molecules and activation of synergistic biologic mechanisms. His studies span basic mechanisms, molecular engineering of new radiopharmaceuticals, radiation dosimetry/pharmacokinetics, and patient therapy. Dr Malik Juweid is Associate Professor of Radiology (Neclear Medicine) at the University of lowa College of Medicine in lowa City, lowa. His interests include radioimmunotherapy and imaging of cancer, in particular non-Hodgkin’s lymphoma, overian and medullary thyroid cancers. His studies involve basic mechanisms, dosimetry and singly- or multicenter clinical trials. Dr Christine White currently serves as Vice President, Clinical Oncology and Hematology for IDEC Pharmaceuticals. Previously, she served as Director of Clinical Oncology Research at the Sidney Kimmel Cancer Center and Sharp Health Care in San Diego, California

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and at Scripps Memorial Hospitals, La Jolla and Encinitas, California. She has also held faculty positions at the University of California, San Diego and is certified by the American Board of Internal Medicine and the American Board of Medical Oncology. Dr Gregory Wiseman is Assistant Professor of Radiology in the Mayo Graduate School of Medicine in Rochester, Minnesota. He is a consultant in the Nuclear Medicine section of the Department of Radiology, where his primary role is clinical imaging and radioisotope therapy. His interests are in the clinical applications of radiopharmaceutical therapy, radiolabeled monoclonal antibodies and peptides. He has worked on treatments for non-Hodgkin’s lymphoma, multiple

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myeloma, renal cell carcinoma, and colorectal carcinoma. Dr Sally DeNardo is a Professor of Internal Medicine and Radiology (Nuclear Medicine) in the Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis School of Medicine, in Sacramento, California, USA. Her interests lie in the development of new therapeutics for breast and prostate cancer and lymphoma using radioisotope conjugated monoclonal antibodies, genetically engineered molecules and activation of synergistic biologic mechanisms. Her studies span basic mechanisms, molecular engineering of new radiopharmaceuticals, in vitro and in vivo tumor cell biology and patient protocol therapy.