Renal uptake of bismuth-213 and its contribution to kidney radiation dose following administration of actinium-225-labeled antibody.

Clinical therapeutic studies using (225)Ac-labeled antibodies have begun. Of major concern is renal toxicity that may result from the three alpha-emitting progeny generated following the decay of (225)Ac. The purpose of this study was to determine the amount of (225)Ac and non-equilibrium progeny in the mouse kidney after the injection of (225)Ac-huM195 antibody and examine the dosimetric consequences. Groups of mice were sacrificed at 24, 96 and 144 h after injection with (225)Ac-huM195 antibody and kidneys excised. One kidney was used for gamma ray spectroscopic measurements by a high-purity germanium (HPGe) detector. The second kidney was used to generate frozen tissue sections which were examined by digital autoradiography (DAR). Two measurements were performed on each kidney specimen: (1) immediately post-resection and (2) after sufficient time for any non-equilibrium excess (213)Bi to decay completely. Comparison of these measurements enabled estimation of the amount of excess (213)Bi reaching the kidney (γ-ray spectroscopy) and its sub-regional distribution (DAR). The average absorbed dose to whole kidney, determined by spectroscopy, was 0.77 (SD 0.21) Gy kBq(-1), of which 0.46 (SD 0.16) Gy kBq(-1) (i.e. 60%) was due to non-equilibrium excess (213)Bi. The relative contributions to renal cortex and medulla were determined by DAR. The estimated dose to the cortex from non-equilibrium excess (213)Bi (0.31 (SD 0.11) Gy kBq(-1)) represented ∼46% of the total. For the medulla the dose contribution from excess (213)Bi (0.81 (SD 0.28) Gy kBq(-1)) was ∼80% of the total. Based on these estimates, for human patients we project a kidney-absorbed dose of 0.28 Gy MBq(-1) following administration of (225)Ac-huM195 with non-equilibrium excess (213)Bi responsible for approximately 60% of the total. Methods to reduce renal accumulation of radioactive progeny appear to be necessary for the success of (225)Ac radioimmunotherapy.

A stereotactic method for the three-dimensional registration of multi-modality biologic images in animals: NMR, PET, histology, and autoradiography.

The objective of this work was to develop and then validate a stereotactic fiduciary marker system for tumor xenografts in rodents which could be used to co-register magnetic resonance imaging (MRI), PET, tissue histology, autoradiography, and measurements from physiologic probes. A Teflon fiduciary template has been designed which allows the precise insertion of small hollow Teflon rods (0.71 mm diameter) into a tumor. These rods can be visualized by MRI and PET as well as by histology and autoradiography on tissue sections. The methodology has been applied and tested on a rigid phantom, on tissue phantom material, and finally on tumor bearing mice. Image registration has been performed between the MRI and PET images for the rigid Teflon phantom and among MRI, digitized microscopy images of tissue histology, and autoradiograms for both tissue phantom and tumor-bearing mice. A registration accuracy, expressed as the average Euclidean distance between the centers of three fiduciary markers among the registered image sets, of 0.2 +/- 0.06 mm was achieved between MRI and microPET image sets of a rigid Teflon phantom. The fiduciary template allows digitized tissue sections to be co-registered with three-dimensional MRI images with an average accuracy of 0.21 and 0.25 mm for the tissue phantoms and tumor xenografts, respectively. Between histology and autoradiograms, it was 0.19 and 0.21 mm for tissue phantoms and tumor xenografts, respectively. The fiduciary marker system provides a coordinate system with which to correlate information from multiple image types, on a voxel-by-voxel basis, with sub-millimeter accuracy--even among imaging modalities with widely disparate spatial resolution and in the absence of identifiable anatomic landmarks.

Relative therapeutic efficacy of (125)I- and (131)I-labeled monoclonal antibody A33 in a human colon cancer xenograft.

UNLABELLED: A33, a monoclonal antibody that targets colon carcinomas, was labeled with (125)I or (131)I and the relative therapeutic efficacy of the 2 radiolabeled species was compared in a human colon cancer xenograft system. METHODS: Nude mice bearing human SW1222 colon carcinoma xenografts were administered escalating activities of (125)I-A33 (9.25-148 MBq) or (131)I-A33 (0.925-18.5 MBq), (125)I- and (131)I-labeled control antibodies, unlabeled antibody, or no antibody. The effects of treatment were assessed using the endpoints of tumor growth delay and cure. RESULTS: Tumor growth delay increased with administered activity for all radiolabeled antibodies. Approximately 4.5 times more activity was required for (125)I-A33 to produce therapeutic effects that were equivalent to those of (131)I-A33. This ratio was approximately 7 for a nonspecific, noninternalizing isotype-matched, radiolabeled control antibody. Unlabeled A33 antibody had no effect on tumor growth. Approximately 10 times more activity of (125)I-A33 produced toxicity similar to that of (131)I-A33, and this ratio fell to approximately 6 for radiolabeled control antibody. CONCLUSION: Treatment with (125)I-A33 resulted in a relative therapeutic gain of approximately 2 compared with (131)I-A33 in this experimental system.

Optimizing the sequence of combination therapy with radiolabeled antibodies and fractionated external beam.

UNLABELLED: The purpose of this study was to determine the optimum sequence for combined modality therapy with radiolabeled antibodies and fractionated external beam radiation. METHODS: The uptake and distribution of a nontherapeutic activity of 125I-labeled tumor-associated A33 monoclonal antibody was determined in SW1222 human colon carcinoma xenografts in nude mice for 4 study groups: group 1, radiolabeled antibody alone; group 2, radiolabeled antibody administered (day 0) immediately before the first of 5 daily fractions of 2-Gy, 320-kilovolt peak x-rays; group 3, radiolabeled antibody administered after the fifth radiation fraction (day 5); and group 4, radiolabeled antibody administered 5 d after irradiation (day 10). Tumors were excised 5 d after antibody administration. Tumors were frozen and sectioned for histology and phosphor plate autoradiography. The percentage of A33 antigen-expressing cells was estimated by immunohistochemical staining. RESULTS: The average tumor uptake values relative to control group 1 were 1.47 (group 2), 0.78 (group 3), and 0.21 (group 4), which illustrates that tumor uptake is increased by almost 50% when the antibody is present in the blood at the start of irradiation. Five days into a fractionated irradiation protocol, antibody uptake was reduced, falling more significantly on day 10. Phosphor plate autoradiographs showed decreased uptake uniformity for groups 3 and 4. Immunohistochemical data showed a reduction in A33 antigen-positive cells from 85%, 64%, 50%, to 41% for groups 1-4, respectively. CONCLUSION: Maximum radiolabeled antibody tumor uptake was achieved when the antibody was administered just before radiation therapy. This might be explained by a transient increase in capillary leakage to macromolecules, followed by a reduction at later times, possibly the result of capillary damage and occlusion.

Single-dose versus fractionated radioimmunotherapy: model comparisons for uniform tumor dosimetry.

UNLABELLED: Targeting molecules with reduced immunogenicity will enable repetitive administrations of radioimmunotherapy. In this work a mathematical model was used to compare 2 different treatment strategies: large single administrations (LSAs) and rapid fractionation (RF) of small individual administrations separated by short time intervals. METHODS: An integrated compartmental model of treatment pharmacokinetics and tumor response was used to compare alternative treatments that delivered identical absorbed doses to red marrow. RESULTS: Based on the key assumption of uniform dose distributions, the LSA approach consistently produced smaller nadir values of tumor cell survival and tumor size. The predicted duration of remission was similar for both treatment structures. These findings held for both macroscopic and microscopic tumors and were independent of tumor cell radiosensitivity, proliferation rate, rate of tumor shrinkage, and uptake characteristics of radiolabeled material in tumor. CONCLUSION: Clinical situations for which each treatment is most appropriate may be tentatively identified. An LSA using a short-range-emitting radionuclide would be most appropriate for therapy of microscopic disease, if uptake is relatively homogeneous. RF using a longer range emitter would be most appropriate for macroscopic disease, if uptake is heterogeneous and varies from one administration to another. There is a rationale for combining LSA and RF treatments in clinical situations in which slowly growing macroscopic disease and rapidly growing microscopic disease exist simultaneously.

131I radioimmunotherapy and fractionated external beam radiotherapy: comparative effectiveness in a human tumor xenograft.

UNLABELLED: This article compares the effectiveness of radiation delivered by a radiolabeled monoclonal antibody, 131I-labeled A33, that targets colorectal carcinoma, with that of 10 fractions of conventional 320 kVp x-rays. METHODS: Human colorectal cancer xenografts (SW1222) ranging between 0.14 and 0.84 g were grown in nude mice. These were treated either with escalating activities (3.7-18.5 MBq) of 131I-labeled A33 or 10 fractions of 320 kVp x-rays (fraction sizes from 1.5 to 5 Gy). Tumor dosimetry was determined from a similar group of tumor-bearing animals by serial kill, tumor resection and counting of radioactivity in a gamma counter. The relative effectiveness of the two radiation therapy treatment approaches was compared in terms of tumor regrowth delay and probability of tumor cure. RESULTS: The absorbed dose to tumor per MBq administered was estimated as 3.7 Gy (+/-1 Gy; 95% confidence interval). We observed a close to linear increase in tumor regrowth delay with escalating administered activity. Equitumor response of 1311 monoclonal antibody A33 was observed at average radiation doses to the tumor three times greater than when delivered by fractionated external beam radiotherapy. The relationship between the likelihood of tumor cure and administered activity was less predictable than that for regrowth delay. CONCLUSION: The relative effectiveness per unit dose of radiation therapy delivered by 131I-labeled A33 monoclonal antibodies was approximately one third of that produced by fractionated external beam radiotherapy, when measured by tumor regrowth delay.

Implications of nonuniform tumor doses for radioimmunotherapy.

UNLABELLED: This article describes a method of assessing the biologic consequences of nonuniform dose distributions produced in tumors by biologically targeted radionuclide therapy. The analysis is based on a simple mathematical model that assumes all tumor cells are uniformly radiosensitive. METHODS: Using the linear-quadratic radiobiologic model, it is possible to represent an absorbed dose distribution by a biologically effective dose (BED) volume histogram (BVH). The Laplace transform of the BVH yields an equivalent uniform biologically effective dose. This is a one-number value that fully describes the biologic effect of a nonuniform absorbed dose distribution. In this article, for the purposes of exposition, nonuniform BED distributions are represented by normal distributions. RESULTS: Nonuniform absorbed dose distributions are inefficient in sterilizing tumors and become proportionately less effective as the mean dose increases. The loss in effectiveness is most severe for radiosensitive tumors. CONCLUSION: Several approaches may alleviate the consequences of dosimetric nonuniformity. These include the use of smaller targeting molecules, radionuclides with longer emission ranges, fractionated administration of biologically targeted radionuclide therapy and combined modality treatments.

Phase I/II radioimmunotherapy trial with iodine-131-labeled monoclonal antibody G250 in metastatic renal cell carcinoma.

This Phase I/II radioimmunotherapy study was carried out to determine the maximum tolerated dose (MTD) and therapeutic potential of 131I-G250. Thirty-three patients with measurable metastatic renal cell carcinoma were treated. Groups of at least three patients received escalating amounts of 1311I (30, 45, 60, 75, and 90 mCi/m2) labeled to 10 mg of mouse monoclonal antibody G250, administered as a single i.v. infusion. Fifteen patients were studied at the MTD of activity. No patient had received prior significant radiotherapy; one had received prior G250. Whole-body scintigrams and single-photon emission computed tomography images were obtained in all patients. There was targeting of radioactivity to all known tumor sites that were > or =2 cm. Reversible liver function test abnormalities were observed in the majority of patients (27 of 33 patients). There was no correlation between the amount of 131I administered or hepatic absorbed radiation dose (median, 0.073 Gy/mCi) and the extent or nature of hepatic toxicity. Two of the first six patients at 90 mCi/m2 had grade > or =3 thrombocytopenia; the MTD was determined to be 90 mCi/m2 131I. Hematological toxicity was correlated with whole-body absorbed radiation dose. All patients developed human antimouse antibodies within 4 weeks posttherapy; retreatment was, therefore, not possible. Seventeen of 33 evaluable patients had stable disease. There were no major responses. On the basis of external imaging, 131I-labeled mouse monoclonal antibody G250 showed excellent localization to all tumors that were > or =2 cm. Seventeen of 33 patients had stable disease, with tumor shrinkage observed in two patients. Antibody immunogenicity restricted therapy to a single infusion. Studies with a nonimmunogenic G250 antibody are warranted.

Mathematical model of 5-[125I]iodo-2'-deoxyuridine treatment: continuous infusion regimens for hepatic metastases.

PURPOSE: Due to the cytotoxicity of DNA-bound iodine-125, 5-[125I]Iodo-2'-deoxyuridine ([125I]IUdR), an analog of thymidine, has long been recognized as possessing therapeutic potential. In this work, the feasibility and potential effectiveness of hepatic artery infusion of [125I]IUdR is examined. METHODS: A mathematical model has been developed that simulates tumor growth and response to [125I]IUdR treatment. The model is used to examine the efficacy and potential toxicity of prolonged infusion therapy. Treatment of kinetically homogeneous tumors with potential doubling times of either 4, 5, or 6 days is simulated. Assuming uniformly distributed activity, absorbed dose estimates to the red marrow, liver and whole-body are calculated to assess the potential toxicity of treatment. RESULTS: Nine to 10 logs of tumor-cell kill over a 7- to 20-day period are predicted by the various simulations examined. The most slowly proliferating tumor was also the most difficult to eradicate. During the infusion time, tumor-cell loss consisted of two components: A plateau phase, beginning at the start of infusion and ending once the infusion time exceeded the potential doubling time of the tumor; and a rapid cell-reduction phase that was close to log-linear. Beyond the plateau phase, treatment efficacy was highly sensitive to tumor activity concentration. CONCLUSIONS: Model predictions suggest that [125I]IUdR will be highly dependent upon the potential doubling time of the tumor. Significant tumor cell kill will require infusion durations that exceed the longest potential doubling time in the tumor-cell population.

Pharmacokinetic model of iodine-131-G250 antibody in renal cell carcinoma patients.

UNLABELLED: A model that describes the pharmacokinetic distribution of 131I-labeled G250 antibody is developed. METHODS: Previously collected pharmacokinetic data from a Phase I-II study of 131I-G250 murine antibody against renal cell carcinoma were used to develop a mathematical model describing antibody clearance from serum and the whole body. Survey meter measurements, obtained while the patient was under radiation precautions, and imaging data, obtained at later times, were combined to evaluate whole-body clearance kinetics over an extended period. RESULTS: A linear two-compartment model was found to provide good fits to the data. The antibody was injected into Compartment 1, the initial distribution volume (Vd) of the antibody, which included serum. The antibody exchanged with the rest of the body, Compartment 2, and was eventually excreted. Data from 13 of the 16 patients fit the model with unique parameters; the maximum, median and minimum values for model-derived Vd were 6.3, 3.7 and 2.11, respectively. The maximum, median and minimum values for the excretion rate were 8 x 10(-2), 2.4 x 10(-2) and 1.3 x 10(-2) hr(-1), respectively. Parameter sensitivity analysis showed that a change in the transfer rate constant from serum to the rest of the body had the greatest effect on serum cumulative activity and that the rate constant for excretion had the greatest effect on whole-body cumulative activity. CONCLUSION: A linear two-compartment model was adequate in describing the serum and whole-body kinetics of G250 antibody distribution. The median initial distribution volume predicted by the model was consistent with the nominal value of 3.81. A wide variability in fitted parameters was observed among patients, reflecting the differences in individual patient clearance and exchange kinetics of G250 antibody. By selecting median parameter values, such a model may be used to evaluate and design prolonged multiple administration radioimmunotherapy protocols.

The response of tumours with Gompertzian growth characteristics to fractionated radiotherapy.

Proliferation of tumour cells during radiotherapy may be a significant factor determining response to treatment. In previous work based on the linear-quadratic (LQ) model, tumour cell proliferation was assumed to be independent of both tumour size and the temporal structure of treatment. This paper examines a form of tumour cell proliferation that is exponential at small tumour sizes and Gompertzian at larger sizes. This is integrated with the LQ description of tumour cell sterilization. It is assumed that exposure to therapeutic radiation changes the state of tumour cells from viable to doomed. Doomed cells are assumed to be lost from the tumour mass with exponential kinetics. Six parameters are used to describe tumour response. Three of these are the standard 'LQ+time' (alpha, beta, Tpot) parameters. Two additional parameters are required to describe the shape of the tumour growth/regrowth curve (VG, Vmax). The sixth parameter (Ts) represents the rate of loss of doomed cells from the tumour. The model may be used to describe the effects of radiation therapy, both in terms of cure response (clonogenic cell sterilization) and also remission response (tumour regression and regrowth). An important feature of the model is that it enables the effects of temporally non-uniform treatments to be described. Preliminary modelling studies suggest that it may be possible to manipulate the temporal structures of fractionation schedules to increase the duration of remission at the expense of the probability of cure.

Calculation of integrated biological response in brachytherapy.

PURPOSE: To present analytical methods for calculating or estimating the integrated biological response in brachytherapy applications, and which allow for the presence of dose gradients. METHODS AND MATERIALS: The approach uses linear-quadratic (LQ) formulations to identify an equivalent biologically effective dose (BEDeq) which, if applied to a specified tissue volume, would produce the same biological effect as that achieved by a given brachytherapy application. For simple geometrical cases, BED multiplying factors have been derived which allow the equivalent BED for tumors to be estimated from a single BED value calculated at a dose reference point. For more complex brachytherapy applications a voxel-by-voxel determination of the equivalent BED will be more accurate. Equations are derived which when incorporated into brachytherapy software would facilitate such a process. RESULTS: At both high and low dose rates, the BEDs calculated at the dose reference point are shown to be lower than the true values by an amount which depends primarily on the magnitude of the prescribed dose; the BED multiplying factors are higher for smaller prescribed doses. The multiplying factors are less dependent on the assumed radiobiological parameters. In most clinical applications involving multiple sources, particularly those in multiplanar arrays, the multiplying factors are likely to be smaller than those derived here for single sources. The overall suggestion is that the radiobiological consequences of dose gradients in well-designed brachytherapy treatments, although important, may be less significant than is sometimes supposed. The modeling exercise also demonstrates that the integrated biological effect associated with fractionated high-dose-rate (FHDR) brachytherapy will usually be different from that for an "equivalent" continuous low-dose-rate (CLDR) regime. For practical FHDR regimes involving relatively small numbers of fractions, the integrated biological effect to tissues close to the treatment sources will be higher with HDR than for LDR. Conversely, the integrated biological effect on structures more distant from the sources will be less with HDR. This provides quantitative confirmation of an idea proposed elsewhere, and suggests the existence of a potentially useful biological advantage for HDR brachytherapy delivered in relatively small fraction numbers and which is not apparent when considering radiobiological effect only at discrete reference points. CONCLUSION: The estimation and direct calculation of integrated biological response in brachytherapy are both relatively straightforward. Although the tabular data presented here result from considering only simple geometrical cases, and may thus overestimate the consequences of dose gradients in multiplanar clinical applications, the methods described may open the way to the development of more realistic radiobiological software, and to more systematic approaches for correlating physical dose and biological effect in brachytherapy.

Targeted radiotherapy using Auger electron emitters.

Auger-emitting radionuclides have potential for the therapy of cancer due to their high level of cytotoxicity and short-range biological effectiveness. Biological effects are critically dependent on the sub-cellular (and sub-nuclear) localization of Auger emitters. Mathematical modelling studies suggest that there are theoretical advantages in the use of radionuclides with short half-lives (such as 123I) in preference to those (such as 125I) with long half-lives. In addition, heterogeneity of radionuclide uptake is predicted to be a serious limitation on the ultimate therapeutic effect of targeted Auger therapy. Possible methods of targeting include the use of analogues of DNA precursors such as iodo-deoxyuridine and molecules which bind DNA such as steroid hormones or growth factors. A longer term possibility may be the use of molecules such as oligonucleotides which can discriminate at the level of DNA sequence. It seems likely that the optimal clinical role of targeted Auger therapy will be as one component of a multi-modality therapeutic strategy for the treatment of selected malignant diseases.

Strategies for selective targeting of Auger electron emitters to tumor cells.

UNLABELLED: Strategies based on the use of Auger-emitting radionuclides require the targeting of genomic DNA. Iododeoxyuridine and its analogs, which target the process of DNA synthesis, are incorporated randomly in the genome. Alternative targeting agents are likely to assume a greater role in the future. One possibility is the use of triplex-forming oligonucleotides to target genomic DNA on a sequence-specific basis. METHODS: A model oligonucleotide-targeting system has been developed using a synthetic DNA target sequence based on the N-myc gene. This has been used to examine the ability of alternative oligonucleotides to form DNA triplexes with homopurine-homopyrimidine tract of the target sequence. RESULTS: Oligonucleotides consisting of G and A or G and T that were designed to bind in an antiparallel orientation to the homopurine strand of the target sequence formed triplexes. CONCLUSION: Triplex-forming oligonucleotides have potential as therapeutic agents for cytotoxic therapy. They may also have applications in the study of microradiobiological questions, such as the radiosensitivity of individual genes. Methods of synthesizing high specific activity triplex-forming oligonucleotides, probably using short half-life radionuclides such as 123I, are required.

Relationships between tumor size and curability for uniformly targeted therapy with beta-emitting radionuclides.

UNLABELLED: Targeted radionuclide therapy is a new form of radiotherapy that differs in some important respects from external beam irradiation. One of the most important differences is due to the finite range of ionizing beta particles emitted as a result of radionuclide disintegration. The effects of particle range have important implications for the curability of tumors. METHODS: We used a mathematical model to examine tumor curability and its relationship to tumor size for 22 beta-emitting radionuclides that may have therapeutic potential. The model assumed a uniform distribution of radionuclide throughout. RESULTS: For targeted radionuclide therapy, the relationship between tumor curability and tumor size is different from that for conventional external beam radiotherapy. With targeted radionuclides, there is an optimal tumor size for cure. Tumors smaller than the optimal size are less vulnerable to irradiation from radionuclides because a substantial proportion of the disintegration energy escapes and is deposited outside the tumor volume. CONCLUSION: We found an optimal tumor size for radiocurability by each of the 22 radionuclides considered. Optimal cure diameters range from less than 1 mm for short-range emitters such as 199Au and 33P to several centimeters for long-range emitters such as 90Y and 188Re. The energy emitted per disintegration may be used to predict optimal cure size for uniform distributions of radionuclide.

Optimum combination of targeted 131I and total body irradiation for treatment of disseminated cancer.

PURPOSE: Radiobiological modeling was used to explore optimum combination strategies for treatment of disseminated malignancies of differing radiosensitivity and differing patterns of metastatic spread. The purpose of the study was to derive robust conclusions about the design of combination strategies that incorporate a targeting component. Preliminary clinical experience of a neuroblastoma treatment strategy, which is based upon general principles obtained from modelling, is briefly described. METHODS AND MATERIALS: The radiobiological analysis was based on an extended (dose-rate dependent) formulation of the linear quadratic model. Radiation dose and dose rate for targeted irradiation of tumors of differing size was in part based on microdosimetric considerations. The analysis was applied to several tumor types with postulated differences in the pattern of metastatic spread, represented by the steepness of the slope of the relationship between numbers of tumors present and tumor diameter. The clinical pilot study entailed the treatment of five children with advanced neuroblastoma using a combination of 131I metaiodobenzylguanidine (mIBG) and total body irradiation followed by bone marrow rescue. RESULTS: The theoretical analysis shows that both intrinsic radiosensitivity and pattern of metastatic spread can influence the composition of the ideal optimum combination strategy. High intrinsic radiosensitivity generally favors a high proportion of targeting component in the combination treatment, while a strong tendency to micrometastatic spread favors a major contribution by total body irradiation. The neuroblastoma patients were treated using a combination regimen with an initially low targeting component (2 Gy whole body dose from targeting component plus 12 Gy from total body irradiation). The treatment was tolerable and resulted in remissions in excess of 9 months in each of these advanced neuroblastoma patients. CONCLUSIONS: Radiobiological analysis, which incorporates simple models of metastatic spread, emphasizes the importance of the total body irradiation component in a targeting/total body irradiation combination strategy. However, the analysis favors a larger targeting component than is used in clinical practice at present. A cautious escalation of the 131I mIBG component in the combination treatment of advanced neuroblastoma appears justified.

Enhanced tumour uptake and in vitro radiotoxicity of no-carrier-added [131I]meta-iodobenzylguanidine: implications for the targeted radiotherapy of neuroblastoma.

In vitro and in vivo neuroblastoma models were used to determine whether improvements in tumour targeting in vivo and therapeutic efficacy in vitro could result from the use of no-carrier-added (n.c.a.) [131I]MIBG. Results were compared with use of the conventional therapy MIBG preparation (ex. [131I]MIBG) of lower specific activity which is produced by iodide exchange reaction. The efficacy of n.c.a. [131I]MIBG was compared with that of [131I]MIBG over a range of specific activities by the assessment of neuroblastoma spheroid growth delay. Whereas n.c.a. [131I]MIBG at a radioactivity concentration of 2 MBq/ml prevented the regrowth of 84% of spheroids, toxicity was significantly reduced by the addition of non-radiolabelled MIBG to the incubation medium. The time-dependent biodistribution of n.c.a. [131I]MIBG in nude mice bearing human neuroblastoma xenografts was compared with that of the conventional therapy radiopharmaceutical. The n.c.a. agent gave improved tumour uptake but also significantly greater accumulation in normal tissues known to accumulate MIBG such as heart, adrenal and skin. However, uptake and retention in the blood was unaltered. For all tissues examined, the 3-day calculations were undertaken to predict organ to tumour dose ratios which would result in human neuroblastoma patients with each of the [131I]MIBG preparations. These results suggest that significant therapeutic gain may be achieved by the use of n.c.a. [131I]MIBG as a treatment agent in neuroblastoma. neuroblastoma.

Multi-modality megatherapy with [131I]meta-iodobenzylguanidine, high dose melphalan and total body irradiation with bone marrow rescue: feasibility study of a new strategy for advanced neuroblastoma.

New therapeutic approaches are needed for advanced neuroblastoma as few patients are currently curable. We describe an innovative strategy combining [131I]meta-iodobenzylguanidine ([131I]mIBG) therapy with high dose chemotherapy and total body irradiation. The aim of combining these treatments is to overcome the specific limitations of each when used alone to maximise killing of neuroblastoma cells. Five children received combined therapy with [131I]mIBG followed by high dose melphalan and fractionated total body irradiation. Autologous bone marrow transplantation was undertaken in 3 patients and allogeneic in 2 patients. One patient received additional localised radiotherapy to residual bulk disease. One patient is alive without relapse 32 months after treatment. 4 patients relapsed after remissions of 9, 10, 14 and 21 months. These results indicate that this combined modality approach is feasible and safe, but further evaluation is necessary to establish whether it has advantages over conventional megatherapy using melphalan alone.

The impact of tumor cell proliferation in radioimmunotherapy.

BACKGROUND: In conventional radiotherapy, proliferation of tumor cells throughout treatment is believed to be an important cause of treatment failure. For radioimmunotherapy (RAIT), tumor cell proliferation will be a significant mechanism to consider when designing therapeutic strategies. METHODS: A mathematic model, based on the irradiation of a proliferating tumor cell population by an exponentially decaying dose-rate, was used to examine the effects of proliferation during RAIT. RESULTS: Proliferation can give rise to dose-rate effects in tumors that are distinct from those attributable to repair or recovery from radiation damage. An equation for the therapeutic efficiency of RAIT was generated. The analysis showed that RAIT will be less effective on rapidly proliferating tumor cell populations. High radioresistance causes a radiation dose to produce less tumor cell sterilization. In addition, for RAIT, the proportion of the dose that is "wasted" because of proliferation will be greater for radioresistant tumors. Therapeutically, higher initial dose-rates are more effective, meaning that, dose for dose, shorter decay half-lives will be better than longer ones. The analysis indicates that the therapeutic efficiency depends on tumor size and dosimetric heterogeneity and implies that micrometastases and "cold spots" in tumors could be major foci of recurrence. CONCLUSIONS: The results of this study support the use of RAIT as part of an integrated treatment regimen featuring local radiotherapy to bulk disease, and systemic treatment with total body irradiation plus bone marrow rescue and/or chemotherapy.