Dosimetry in patients with B-cell lymphoma treated with [(90)Y]ibritumomab tiuxetan or [(131)I]tositumomab.

Radioimmunotherapy involves the use of radiolabeled monoclonal antibodies (MAbs) to treat malignancy. The therapeutic effect is determined by the radiopharmaceutical, the radiation absorbed dose and previous treatments. There are currently two approved radiopharmaceuticals for the treatment of B-cell lymphoma - the (90)Y-labeled ibritumomab and the (131)I-labeled tositumomab. Both are directed against CD20, albeit not against the same epitope. This paper summarizes current results of dose-responses for normal tissues and tumours of [(131)I]tositumomab and [(90)Y]ibritumomab tiuxetan, discusses them in the context of dosimetry methods used and highlights the assumptions being made in the different dosimetry methodologies. Moreover, we wish to point at the possibility of performing low-cost therapy bremsstrahlung imaging for [(90)Y]ibritumomab tiuxetan to confirm biodistribution, and possibly also for dosimetric calculations.

Guidelines for radioiodine therapy of differentiated thyroid cancer.

INTRODUCTION: The purpose of the present guidelines on the radioiodine therapy (RAIT) of differentiated thyroid cancer (DTC) formulated by the European Association of Nuclear Medicine (EANM) Therapy Committee is to provide advice to nuclear medicine clinicians and other members of the DTC-treating community on how to ablate thyroid remnant or treat inoperable advanced DTC or both employing large 131-iodine ((131)I) activities. DISCUSSION: For this purpose, recommendations have been formulated based on recent literature and expert opinion regarding the rationale, indications and contraindications for these procedures, as well as the radioiodine activities and the administration and patient preparation techniques to be used. Recommendations also are provided on pre-RAIT history and examinations, patient counselling and precautions that should be associated with (131)I iodine ablation and treatment. Furthermore, potential side effects of radioiodine therapy and alternate or additional treatments to this modality are reviewed. Appendices furnish information on dosimetry and post-therapy scintigraphy.

Targeted therapy in nuclear medicine--current status and future prospects.

In recent years, a number of new developments in targeted therapies using radiolabeled compounds have emerged. New developments and insights in radioiodine treatment of thyroid cancer, treatment of lymphoma and solid tumors with radiolabeled monoclonal antibodies (mAbs), the developments in the application of radiolabeled small receptor-specific molecules such as meta-iodobenzylguanidine and peptides and the position of locoregional treatment in malignant involvement of the liver are reviewed. The introduction of recombinant human thyroid-stimulating hormone and the possibility to enhance iodine uptake with retinoids has changed the radioiodine treatment protocol of patients with thyroid cancer. Introduction of radiolabeled mAbs has provided additional treatment options in patients with malignant lymphoma, while a similar approach proves to be cumbersome in patients with solid tumors. With radiolabeled small molecules that target specific receptors on tumor cells, high radiation doses can be directed to tumors in patients with disseminated disease. Radiolabeled somatostatin derivatives for the treatment of neuroendocrine tumors are the role model for this approach. Locoregional treatment with radiopharmaceuticals of patients with hepatocellular carcinoma or metastases to the liver may be used in inoperable cases, but may also be of benefit in a neo-adjuvant or adjuvant setting. Significant developments in the application of targeted radionuclide therapy have taken place. New treatment modalities have been introduced in the clinic. The concept of combining therapeutic radiopharmaceuticals with other treatment modalities is more extensively explored.

Clinical radionuclide therapy dosimetry: the quest for the "Holy Gray".

INTRODUCTION: Radionuclide therapy has distinct similarities to, but also profound differences from external radiotherapy. REVIEW: This review discusses techniques and results of previously developed dosimetry methods in thyroid carcinoma, neuro-endocrine tumours, solid tumours and lymphoma. In each case, emphasis is placed on the level of evidence and practical applicability. Although dosimetry has been of enormous value in the preclinical phase of radiopharmaceutical development, its clinical use to optimise administered activity on an individual patient basis has been less evident. In phase I and II trials, dosimetry may be considered an inherent part of therapy to establish the maximum tolerated dose and dose-response relationship. To prove that dosimetry-based radionuclide therapy is of additional benefit over fixed dosing or dosing per kilogram body weight, prospective randomised phase III trials with appropriate end points have to be undertaken. Data in the literature which underscore the potential of dosimetry to avoid under- and overdosing and to standardise radionuclide therapy methods internationally are very scarce. DEVELOPMENTS: In each section, particular developments and insights into these therapies are related to opportunities for dosimetry. The recent developments in PET and PET/CT imaging, including micro-devices for animal research, and molecular medicine provide major challenges for innovative therapy and dosimetry techniques. Furthermore, the increasing scientific interest in the radiobiological features specific to radionuclide therapy will advance our ability to administer this treatment modality optimally.

Rat testis as a radiobiological in vivo model for radionuclides.

The radiobiological effect of intracellularly localised radionuclides emitting low energy electrons (Auger electrons) has received much attention. Most in vivo studies reported have been performed in the mouse testis. We have investigated the rat testis as an in vivo radiobiological model, with sperm-head survival, testis weight loss and also alteration in the blood plasma hormone levels of FSH and LH as radiobiological endpoints. Validation of the rat testis model was evaluated by using mean absorbed doses of up to 10 Gy from intratesticularly (i.t.) injected (111)In oxine or local X-ray irradiation. Biokinetics of the i.t. injected radionuclide was analysed by scintillation camera imaging and used in the absorbed dose estimation. By the analysis of the autoradiographs, the activity distribution was revealed. Cell fractionation showed (111)In to be mainly associated with the cell nuclei. External irradiations were monitored by thermoluminescence dosimeters. The sperm-head survival was the most sensitive radiobiological parameter correlated to the mean absorbed dose, with a D(37) of 2.3 Gy for (111)In oxine and 1.3 Gy for X rays. The levels of plasma pituitary gonadal hormones FSH and LH were elevated for absorbed doses >7.7 Gy. This investigation shows that the radiobiological model based on the rat testis has several advantages compared with the previously commonly used mouse testis model. The model is appropriate for further investigations of basic phenomena such as radiation geometry, intracellular kinetics and heterogeneity, crucial for an understanding of the biological effect of low-energy electrons.

Anaplastic giant cell thyroid carcinoma.

Anaplastic (giant cell) thyroid carcinoma (ATC), is one of the most aggressive malignancies in humans with a median survival time after diagnosis of 3-6 months. Death from ATC was earlier seen because of local growth and suffocation. ATC is uncommon, accounting for less than 5 % of all thyroid carcinomas. The diagnosis can be established by means of multiple fine needle aspiration biopsies, which are neither harmful nor troublesome for the patient. The cytological diagnosis of this high-grade malignant tumour is usually not difficult for a well trained cytologist. The intention to treat patients with ATC is cure, although only few of them survive. The majority of the patients are older than 60 years and treatment must be influenced by their high age. We have by using a combined modality regimen succeeded in achieving local control in most patients. Every effort should be made to control the primary tumour and thereby improve the quality of remaining life and it is important for patients, relatives and the personnel to know that cure is not impossible. Different treatment combinations have been used since 30 years including radiotherapy, cytostatic drugs and surgery, when feasible. In our latest combined regimen, 22 patients were treated with hyper fractionated radiotherapy 1.6Gy x 2 to a total target dose of 46 Gy given preoperatively, 20 mg doxorubicin was administered intravenously once weekly and surgery was carried out 2-3 weeks after the radiotherapy. 17 of these 22 patients were operated upon and none of these 17 patients got a local recurrence. In the future we are awaiting the development of new therapeutic approaches to this aggressive type of carcinoma. Inhibitors of angiogenesis might be useful. Combretastatin has displayed cytotoxicity against ATC cell lines and has had a positive effect on ATC in a patient. Sodium iodide symporter (NIS) genetherapy is also being currently considered for dedifferentiated thyroid carcinomas with the ultimate aim of making radio-iodine therapy possible.

Anaplastic thyroid carcinoma: three protocols combining doxorubicin, hyperfractionated radiotherapy and surgery.

Patients with anaplastic thyroid carcinoma can rarely be cured, but every effort should be made to prevent death due to suffocation. Between 1984 and 1999, 55 consecutive patients with anaplastic thyroid carcinoma were prospectively treated according to a combined regimen consisting of hyperfractionated radiotherapy, doxorubicin, and when feasible surgery. Radiotherapy was carried out for 5 days a week. The daily fraction until 1988 was 1.0 Gyx2 (A) and 1989-92 1.3 Gyx2 (B). Thereafter 1.6 Gyx2 (C) was administered. Radiotherapy was administered to a total target dose of 46 Gy; of which 30 Gy was administered preoperatively in the first two protocols (A and B), while the whole dose was given preoperatively in the third protocol (C). The therapy was otherwise identical. Twenty mg doxorubicin was administered intravenously weekly. Surgery was possible in 40 patients. No patient failed to complete the protocol due to toxicity. In only 13 cases (24%) was death attributed to local failure. Five patients (9%) 'had a survival' exceeding 2 years. No signs of local recurrence were seen in 33 patients (60%); 5 out of 16 patients in Protocol A, 11 out of 17 patients in Protocol B, 17 out of 22 patients in Protocol C (P=0.017). In the 40 patients undergoing additional surgery, no signs of local recurrence were seen in 5 out of 9 patients, 11 out of 14 patients and 17 out of 17 patients, respectively (P=0.005).

A Swedish study of chemoradiation in squamous cell carcinoma of the esophagus.

This multicenter study describes the development of a chemoradiation protocol for the treatment of non-metastatic squamous cell carcinoma of the esophagus. Eighty patients were treated with three courses of chemotherapy (cisplatinum and 5-fluorouracil) with concomitant radiotherapy (40 Gy) during the last two courses of chemotherapy. Esophagectomy was performed, when feasible. If no operation was performed, patients were planned to receive a target dose of 64 Gy. Toxicity was mainly attributable to hematological impairment and led to two adjustments of the treatment protocol (addition of filgrastim and lowering of the 5-fluorouracil dose). These changes made it possible to administer the planned treatment in a gradually higher proportion of patients (13/23 [57%] before changes of treatment compared with 30/36 [83%] after changes). Treatment-related mortality was 3.75% (3 patients, associated with leucopenic septicemia after chemotherapy). Fifty-four patients were resected. No per- or postoperative mortality was encountered. The complete response (pathological CR) rate in operated patients was 46% (27/59 patients) after chemoradiation. In the whole series the CR rate (including clinical CR for non-resected patients) was 44%. With a minimum follow-up of 37 months, the 3-year survival for the whole group was 31% compared with 57% for the CR patients. Total 5-year survival thus far (July 1999) is 26%.

Prognostic value of histopathological response to radiotherapy and microvessel density in oral squamous cell carcinomas.

The prognostic value of histopathological response to preoperative radiotherapy (50 Gy) in radically resected oral carcinomas was studied in 39 consecutive patients. Microvessel density (MVD) was evaluated for relation to radioresponse and outcome. Resected tumour tissue was examined histopathologically and response to radiotherapy was scored according to induced morphological changes. Pretreatment biopsies were stained with antibodies to von Willebrand factor to evaluate MVD in hot-spot regions, in stromal tissue and in tumour epithelial tissue. Histopathological response to radiotherapy was highly prognostic of local failures and survival (p = 0.002), though microscopic surgical radicality was obtained. In good responders to preoperative radiotherapy, the 5-year survival rate was 68% compared with 24% in poor responders. In 12 patients with local recurrence after radical surgery, 11 had poor histopathological radiotherapy responses. In univariate analysis, a high MVD score in tumour epithelium was associated with poor clinical outcome but MVD did not correlate with histopathological radiotherapy response.

Palliative radiation with a radiolabeled diphosphonate (rhenium-186 etidronate) in patients with hormone-refractory disseminated prostate carcinoma.

MATERIAL AND METHODS: The present study investigates the safety and efficacy of 2590 MBq rhenium-186 (186Re) etidronate (i.e. twice the activity normally used) administered intravenously in 15 patients with disseminated prostatic carcinoma and bone pain. RESULTS: Pain relief was observed in 11 of 14 evaluable patients (79%), 4 of whom became completely free from pain. Five of the responding patients also noted an improvement in daily activity and two found it possible to reduce or discontinue morphine medication. Pain relief occurred within one week in four patients, and within two weeks in eight of the responding patients. The mean duration of pain relief after the first course of 186Re-etidronate was 6 weeks (range 4-10). The toxicity was mild (< or = grade 2), transient, and restricted to hematological toxicity. CONCLUSIONS: 186Re-etidronate provided rapid pain-relief and had mild toxicity in most patients with disseminated hormone-refractory prostatic carcinoma, but doubling the activity did not markedly improve the efficacy.

Comparison of 125I- and (111)In-labeled monoclonal antibody BR96 for tumor targeting in combination with extracorporeal immunoadsorption.

Extracorporeal whole blood immunoadsorption (ECIA) accelerates the clearance of radiolabeled monoclonal antibodies (mAbs) without significantly affecting tumor uptake by removing the excess of these mAbs from the blood, thus increasing tumor:normal tissue (T:N) ratios. The present study is focused on comparing the capacity of ECIA in tumor targeting with the same mAb (chiBR96-biotin) labeled with either (111)In or 125I. Forty-five Brown Norwegian rats with syngeneic rat colon carcinoma isografted both in liver and intramuscularly were used. chiBR96 is a highly tumor-specific mAb directed against the Lewis-type antigen. ECIA of whole blood was started 15 h after the injection of 125I- or (111)In-labeled BR96-biotin. The procedure lasted for 2 h and was repeated for (111)In-labeled BR96-biotin in a few rats after 3 or 24 h. ECIA reduced the whole body activity by the same magnitude (between 39% and 52%), irrespective of whether (111)In- or 125I-labeled chiBR96 was used. A similar observation was also made for the reduction in blood radioactivity after ECIA (79-94%). Time-activity curves during ECIA showed that the major reduction (approximately 85%) in blood radioactivity occurred during the first 45-60 min. Repeating the ECIA with (111)In-BR96 caused only an additional minimal reduction of blood activity, whereas a further reduction of whole body activity of 14-20% was achieved. The T:N uptake ratios were significantly enhanced immediately after ECIA with (111)In- or 125I-labeled chiBR96. Due to greater accumulation of (111)In-BR96 in tumors, a long-term improvement in T:N ratios was obtained after ECIA compared with 125I-labeled BR96. Our results therefore indicate that (111)In/(90Y)-labeled BR96-biotin could be more advantageous than 125I/131I for radioimmunotargeting/radioimmunotherapy in combination with ECIA due to better activity retention by the tumor.

Radioimmunotherapy using 131I-labeled anti-CD22 monoclonal antibody (LL2) in patients with previously treated B-cell lymphomas.

Experience in using rapidly internalizing antibodies, such as the anti-CD22 antibody, for radioimmunotherapy of B-cell lymphomas is still limited. The present study was conducted to assess the efficacy and toxicity of a 131I-labeled anti-CD22 monoclonal antibody (mAb), LL2, in patients with B-cell lymphomas failing first- or second-line chemotherapy. Eligible patients were required to have measurable disease, less than 25% B cells in unseparated bone marrow, and an uptake of 99mTc-labeled LL2Fab' in at least one lymphoma lesion on immunoscintigram. Eight of nine patients examined with immunoscintigraphy were unequivocally found to have an uptake, and therapy with 131I-labeled anti-CD22 [1330 MBq/m2 (36 mCi/m2)] preceded by 20 mg of naked anti-CD22 mAb was administered. Three patients achieved partial remission (duration, 12, 3, and 2 months), and one patient with progressive lymphoma showed stable disease for 17 months. Four patients exhibited progressive disease. The toxicity was hematological. Patients with subnormal counts of neutrophils or platelets before therapy seemed to be more at risk for hematological side effects. Radioimmunotherapy in patients with B-cell lymphomas using 131I-labeled mouse anti-CD22 can induce objective remission in patients with aggressive as well as indolent lymphomas who have failed prior chemotherapy.

Hyperthyroidism after surgery for primary hyperparathyroidism.

BACKGROUND: The coexistence of hyperthyroidism and primary hyperparathyroidism (pHPT) has been reported. We have questioned whether hypercalcemia or surgical trauma contribute to transient hyperthyroidism following parathyroid surgery. METHODS: Twenty-six pHPT and eleven breast cancer patients were compared regarding pre-, peri- and postoperative thyrotropin (TSH), free thyroxine (T4) and free triiodothyronine (T3) concentrations. Thyroglobulin concentration, occurrence of autonomous thyroid nodules, and variables reflecting surgical trauma were compared in pHPT patients with and without postoperative hyperthyroidism. RESULTS: Postoperatively, eleven pHPT patients demonstrated T4 and T3 concentrations above normal, and nine developed symptoms of mild thyrotoxicosis. A parallel rise in TSH and T4 concentrations was seen during both parathyroid and breast cancer surgery. Compared with patients with no postoperative hyperthyroidism, patients with postoperative hyperthyroidism showed a parallel rise in mean thyroglobulin and T4/T3 concentrations as well as higher thyroglobulin concentrations. However, there was no difference in variables assessing surgical trauma nor in occurrence of autonomous thyroid nodules. The peri-operative rise in TSH was preceded by a decrease in calcium. CONCLUSION: Transient hyperthyroidism after parathyroid surgery is not infrequent. The condition seems to be self-limiting, since symptoms invariably subsided without treatment. Manipulation of the thyroid gland is most likely the major contributing factor to postoperative hyperthyroidism. However, it may not be the sole explanation, since our data suggest a more multifactorial scenario.

Anaplastic giant cell carcinoma of the thyroid gland: treatment and survival over a 25-year period.

Anaplastic giant cell carcinoma of the thyroid is a rare but highly malignant tumor. At the Karolinska Hospital in Stockholm, surgery, chemotherapy, and radiotherapy have been used separately or in various combinations in 81 patients admitted with this diagnosis during 1971-1997. In this study, we present the various multimodality treatment regimens and their changes over the years and the subsequent differences in survival and local tumor control. Overall, eight patients (10%) survived more than 2 years. All survivors were treated with combinations of chemotherapy, radiotherapy, and surgery. Among the patients who died, local tumor control was achieved by the therapy given in many cases. The results suggest that our current strategy with a combination of preoperative hyperfractionated accelerated radiotherapy, doxorubicin pre- and postoperatively, and debulking surgery whenever possible results in better local tumor control and an increased chance of survival.

Improving tumor-to-normal-tissue ratios of antibodies by extracorporeal immunoadsorption based on the avidin-biotin concept: development of a new treatment strategy applied to monoclonal antibodies murine L6 and chimeric BR96.

BACKGROUND: Several strategies have been explored to accelerate monoclonal antibody (MAb) conjugate clearance without affecting intratumoral uptake. One of the most promising is extracorporeal immunoadsorption (ECIA), in which excess radiolabeled MAb circulating in blood is removed. METHODS: Extracorporeal immunoadsorption (ECIA) based on the avidin-biotin concept enables direct adsorption of radiolabeled and biotinylated MAb from plasma and consequently increases the tumor-to-normal-tissue uptake ratio by reducing background radioactivity in all radiosensitive organs. Because the concept is based on an antibody's being biotinylated prior to injection, the blood clearance efficiency is independent of the idiotype or isotype of the antibody employed. As a result, there is no need to develop new adsorption columns for each antibody system used. We have technically simplified the method recently by removing biotinylated MAb directly from blood without separation from plasma preceding the removal. The current study focused on both the development of ECIA and evaluating the effects of ECIA in terms of tumor targeting with two biotinylated radiolabeled MAbs that have different biokinetics, namely, murine MAb L6 and chimeric Mab BR96. RESULTS: The start time of ECIA should be determined for each MAb individually before radioimmunotherapy and be based on previous tumor biokinetics. BR96 with rapid tumor targeting seems more suitable than L6 for the ECIA procedure; it allows the procedure to start earlier and thereby further reduce whole body activity and exposure of critical organs to radiation. CONCLUSIONS: ECIA enables direct adsorption of radiolabeled and biotinylated monoclonal antibody from blood and consequently increases the tumor-to-normal-tissue uptake ratio. The method is even applicable to both the internalizing and already highly tumor-selective BR96 in a syngeneic tumor model.

Painful bone metastases in hormone-refractory prostate cancer: economic costs of strontium-89 and/or external radiotherapy.

OBJECTIVES: In a prospective randomized Canadian trial, addition of radionuclide strontium (89Sr) to external radiotherapy (ER) was found to prolong the time to further ER by 15 weeks (35 versus 20, P = 0.006) compared to ER alone in patients with hormone-refractory metastatic prostate cancer (HRMPC). The total direct lifetime costs within the Swedish health care system for the following two treatment strategies was estimated as follows: (a) ER initially and in the event of relapse and (b) ER + 89Sr initially and ER in the event of relapse. METHODS: Calculation of lifetime costs was based on the initial total treatment cost and the probability of future treatment costs. In a retrospective analysis, the average cost of a relapse treated with ER alone was calculated from the actual care consumption of 79 consecutive patients from the south of Sweden who received ER because of skeletal pain due to HRMPC. The costs related to ER included skeletal scintigraphy, ER, outpatient visits, inpatients days, and travel to the treatment center. When 89Sr was added, the cost also included the radionuclide and its administration. Costs in Swedish currency (SEK) were based on the regional tariff for 1993 (U.S. $1 = SEK 8.30). RESULTS: The initial cost for one relapse treated with ER alone was estimated to be SEK 31,011 (U.S. $3736) per patient resident within county (close to hospital) and SEK 48,585 (U.S. $5854) per patient resident out of county (far from hospital). The corresponding figure for initial addition of 89Sr to ER was SEK 43,426 (U.S. $5232) and 61,000 (U.S. $7349), respectively. However, comparison between estimated lifetime cost for the two treatment strategies indicated potential cost savings with initial addition of 89Sr to 3% SEK 2720 (U.S. $328) and 7% SEK 11,290 (U.S. $1360), respectively. CONCLUSIONS: Strontium-89 as initial supplement to ER for palliation of pain in HRMPC is beneficial both from the patient and lifetime health service costs perspectives.

Sestamibi versus thallium subtraction scintigraphy in parathyroid localization: a prospective comparative study in patients with predominantly mild primary hyperparathyroidism.

BACKGROUND: Technetium 99m sestamibi was recently introduced for the preoperative localization of abnormal parathyroid glands in patients with primary hyperparathyroidism with promising results. However, the sensitivity of sestamibi and thallium to detect abnormal parathyroid glands is partly dependent on the gland size. In this study we compared the sensitivity of sestamibi subtraction scintigraphy with thallium subtraction scintigraphy in patients with predominantly mild increase in serum calcium level. METHODS: Thirty-nine patients with primary hyperparathyroidism were included. The mean (+/-SD) serum level of calcium was 2.75 +/- 0.17 mmol/L. In 28 (72%) of the patients the serum level of calcium was less than 2.85 mmol/L. These patients were classified as having mild abnormalities in serum calcium. All patients were investigated before operation with both sestamibi and thallium subtraction scintigraphy. RESULTS: In two patients autonomous thyroid adenomas precluded subtraction scintigraphy. Sestamibi subtraction scintigraphy correctly localized 31 (86%) of 36 parathyroid adenomas compared with only 17 (47%) of 36 by thallium subtraction scintigraphy (p < 0.001). There was one false-positive result in the sestamibi group because of a thyroid adenoma, and two of the scans were negative. Both the sestamibi and the thallium subtraction scintigraphy localized one single enlarged gland in all three patients with multiple gland involvement. In no case was multiglandular disease predicted. CONCLUSIONS: Sestamibi subtraction scintigraphy is superior to thallium subtraction scintigraphy and has a high sensitivity to localize a solitary parathyroid adenoma in patients with mild increase in serum calcium level. The sensitivity decreases in patients with multiglandular parathyroid disease and concomitant thyroid nodular abnormalities.

Extracorporeal whole-blood immunoadsorption enhances radioimmunotargeting of iodine-125-labeled BR96-biotin monoclonal antibody.

UNLABELLED: This study investigates the efficacy of tumor radioimmunotargeting with 125I-labeled BR96-biotin monoclonal antibody using a new method, whole-blood immunoadsorption (WBIA), based on direct adsorption of unbound monoclonal antibody (MAb) from blood without preceding separation of plasma. METHODS: Highly tumor-reactive, internalizing, chimeric BR96 MAb of isotype IgG1 binds to a tumor-associated Lewis-type (Le(Y)) cell surface antigen. Forty-six Brown Norwegian male rats were inoculated intramuscularly and beneath the liver or kidney capsule with syngeneic rat colon carcinoma BN7005, expressing Lewis-type antigen, and investigated. The rats were injected intravenously with 3.5-4.5 MBq 125I-labeled BR96-biotin. Twenty of the rats underwent WBIA starting 5 or 12 hr after injection. About six blood volumes were passed through an avidin-gel adsorption column during 2 hr. RESULTS: By using WBIA, whole-body radioactivity was reduced by 50%, and plasma activity by 85%. Both directly after completion of WBIA and 33 hr later, the activity uptake in tumors manifested only a nonsignificant decrease as compared with corresponding controls (p > 0.05) and had approximately similar time-activity curves. Uptake ratios for tumor (T):bone marrow, T:liver, T:kidney and T:lung were enhanced 2.3- to 3.5-fold in all three tumor models, as compared with controls. The ratio of liver tumor to bone marrow was improved from 10:1 to 30:1. CONCLUSION: This new method of WBIA yields significantly improved radioimmunotargeting of highly tumor-reactive, internalizing MAb BR96.