67Cu-versus 131I-labeled Lym-1 antibody: comparative pharmacokinetics and dosimetry in patients with non-Hodgkin's lymphoma.

Antilymphoma mouse monoclonal antibody (MoAb) Lym-1, labeled with 67Cu or 131I, has demonstrated promising results in radioimmunotherapy (RIT) for lymphoma. Although 131I has played a central role in RIT thus far, some properties of 67Cu are preferable. A subset of our patients received both 67Cu- and 131I-labeled Lym-1, allowing a comparative evaluation of the two radiopharmaceuticals administered to a matched population of patients. Four patients with B-lymphocytic non-Hodgkin's lymphoma that had progressed despite standard therapy entered trials of 67Cu- and 131I-labeled Lym-1, which were injected 3-26 days apart. Lym-1 was conjugated to 6-[p-(bromoacetamido)benzyl]-1,4,7,11-tetraazacyclotetradecane-N,N ',N",N'"-tetraacetic acid (BAT) via 2-iminothiolane (2IT) and radiolabeled with 67Cu to prepare 67Cu-2IT-BAT-Lym-1; 131I-Lym-1 was preparred by the chloramine-T reaction. Planar imaging was used to quantitate 67Cu-2IT-BAT-Lym-1 or 131I-Lym-1 in organs and tumors daily for 3 days or longer. 67Cu-2IT-BAT-Lym-1 exhibited higher peak concentration in 92% (12 of 13) of tumors and a longer biological half-time in every tumor than 131I-Lym-1. The mean tumor concentration (%ID/g) of 67Cu-2IT-BAT-Lym-1 was 1.7, 2.2, and 2.8 times that of 131I-Lym-1 at 0, 24, and 48 h after injection, respectively. The mean biological half-times of 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 in tumor were 8.8 and 2.3 days, respectively. Consequently, the mean tumor radiation dose delivered by 67Cu-2IT-BAT-Lym-1 was twice that of 131I-Lym-1, 2.8 (range 0.8-6.7), and 1.4 (range 0.4-35) Gy/GBq, respectively. 67Cu-2IT-BAT-Lym-1 delivered a lower marrow radiation dose than 131I-Lym-1; hence, the tumor:marrow therapeutic indices were 29 and 9.7, respectively. Radiation doses from 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 to normal tissues were similar except for liver, which received a higher dose from 67Cu-2IT-BAT-Lym-1. Images obtained with 67Cu-2IT-BAT-Lym-1 were superior. Radiation dosimetry data for 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 agreed with corresponding data from the larger populations of patients from which the matched population for the current study was drawn. In conclusion, 67Cu-2IT-BAT-Lym-1 given to non-Hodgkin's lymphoma patients in close temporal proximity to 131I-Lym-1 exhibited greater uptake and longer retention in tumor, resulting in higher radiation dose and therapeutic index than 131I-Lym-1. These as well as other factors suggest that 67Cu-2IT-BAT-Lym-1 may be superior to 131I-Lym-1 for RIT.

Planar gamma camera imaging and quantitation of yttrium-90 bremsstrahlung.

UNLABELLED: Yttrium-90 is a promising radionuclide for radioimmunotherapy of cancer because of its energetic beta emissions. Therapeutic management requires quantitative imaging to assess the pharmacokinetics and radiation dosimetry of the 90Y-labeled antibody. Conventional gamma photon imaging methods cannot be easily applied to imaging of 90Y-bremsstrahlung because of its continuous energy spectrum. METHODS: The sensitivity, resolution and source-to-background signal ratio (S/B) of the detector system for 90Y-bremsstrahlung were investigated for various collimators and energy windows in order to determine optimum conditions for quantitative imaging. After these conditions were determined, the accuracy of quantitation of 90Y activity in an Alderson abdominal phantom was examined. RESULTS: When the energy-window width was increased, the benefit of increased sensitivity outweighed degradation in resolution and S/B ratio until the manufacturer's energy specifications for the collimator were exceeded. Using the same energy window, we improved resolution and S/B for the medium-energy (ME) collimator when compared to the low-energy, all-purpose (LEAP) collimator, and there was little additional improvement using the high-energy (HE) collimator. Camera sensitivity under tissue equivalent conditions was 4.2 times greater for the LEAP and 1.7 times greater for the ME collimators when compared to the HE collimator. Thus, the best, most practical selections were found to be the ME collimator and an energy window of 55-285 keV. When we used these optimal conditions for image acquisition, the estimation of 90Y activity in organs and tumors was within 15% of the true activities. CONCLUSIONS: The results of this study suggest that reasonable accuracy can be achieved in clinical radioimmunotherapy using 90Y-bremsstrahlung quantitation.

Prediction of myelotoxicity using radiation doses to marrow from body, blood and marrow sources.

UNLABELLED: Bone marrow is generally the dose-limiting organ in radioimmunotherapy (RIT). Although radiation doses to marrow estimated from tracer doses have been shown to be comparable to those from therapy doses of radionuclide, the correlation of marrow radiation dose and myelotoxicity has not been well documented. The purpose of this study was to evaluate the relationship between radiation dose to marrow and subsequent changes in peripheral blood cell counts. METHODS: Radiation doses to marrow from three sources, body, blood and marrow targeting, were compared with changes in blood counts after the first therapy dose of (131)I-Lym-1 in 16 patients. Doses of (131)I-Lym-1 ranged from 1.1-8.2 GBq (29-222 mCi). Cumulated radioactivity in the body and marrow were obtained using sequential, quantitative images of the body and lumbar vertebrae, respectively, and that in blood using activity in blood samples. The individual and sum of radiation doses from penetrating radiations in the body, and nonpenetrating radiations in the blood and marrow, were compared with blood counts. RESULTS: In this group of patients, median radiation doses were 15.1, 15.4 and 42.1 cGy from body, blood and marrow targeting, respectively. Linear regression of radiation doses from body and blood versus fractional decreases in blood counts produced correlation coefficients of 0.38, 0.06, 0.22 and less than 0.01 for platelets, granulocytes, white blood cells (WBCs) and hematocrit, respectively. Linear regression of targeted marrow radiation doses versus fractional decreases in blood counts produced correlation coefficients 0.61, 0.31, 0.54 and 0.20 for platelets, granulocytes, WBCs and hematocrit. The closest association was found between radiation dose to marrow from marrow targeting and change in platelet count (r = 0.61). CONCLUSION: In patients, such as those with non-Hodgkin's lymphoma (NHL), likely to have marrow targeting, prediction of myelotoxicity by conventional body and blood contributions to marrow is substantially improved by the use of radiation dose to marrow estimated from images.

Prediction of myelotoxicity using semi-quantitative marrow image scores.

UNLABELLED: Marrow radiation with resultant myelosuppression is usually dose-limiting in radioimmunotherapy (RIT). This study evaluated the relationship between a semiquantitative score of radiolabeled antibody marrow uptake obtained by imaging and subsequent decrease in peripheral blood cell counts in a patient population in whom marrow malignancy is common. METHODS: Semiquantitative scores were assigned to lumbar marrow images of 18 patients acquired 0, 6, 24 and 48 hr after the first therapy dose of 131I-Lym-1. Scores were adjusted for injected dose (GBq) and body surface area (m2), and correlated with post-therapy blood counts. A well-defined scale, where 0 and 4 represented least to highest marrow uptake when compared to background, was used to assign marrow image scores. Injected doses of 131I-Lym-1 ranged from 1.1-8.2 GBq (29-222 mCi). RESULTS: Linear regression of summed marrow scores (0-24 hr after injection) versus decrease in cell counts produced correlation coefficients of 0.76, 0.44, 0.58 and 0.46 for platelets, granulocytes, white blood cells (WBC) and hematocrit, respectively. Scores for individual and other combinations of images obtained immediately up to 24 hr after injection were also predictive.

Dosimetric evaluation of copper-64 in copper-67-2IT-BAT-Lym-1 for radioimmunotherapy.

UNLABELLED: Copper-67 (67Cu) is an attractive radionuclide for radioimmuno-therapy because of its favorable physical and biologic characteristics. Current supplies of 67Cu, however, contain as much as 60% of 64Cu at the time of delivery. Scatter photons from 64Cu enter the 67Cu energy window, affecting image resolution and counting accuracy. The radiation dose to tissue is also altered. METHODS: A line source and a small vial source of 67Cu containing varying amounts of 64Cu were used to evaluate the impact of 64Cu on image resolution and activity quantitation, respectively. Identical pharmacokinetics for 67Cu and 64Cu was assumed, and the radiation dosimetry of 64Cu was assessed using quantitative imaging data for 67Cu because the amount of 64Cu could be calculated for any time after 67Cu production. MIRD formalism was used to estimate the therapeutic index, defined as the ratio of radiation dose to tumor divided by the radiation dose to bone marrow. RESULTS: As the amount of 64Cu increased, the full width at tenth maximum of the line spread function increased, although there was no significant change in full width at half maximum. The number of scatter counts from 64Cu increased as the amount of 64Cu or the size of the source region of interest increased. When 64Cu was 25% of the total activity, less than 10% of the total 67Cu photopeak counts detected with a scintillation camera were attributable to 64Cu. Although the tumor radiation dose per unit of activity (cGy/GBq) from 67Cu was five times greater than that from 64Cu, the marrow dose (CGy/GBq) from 67Cu was only three times greater than that from 64Cu. Therefore, the therapeutic index was diminished by the presence of 64Cu. When 64Cu radioimpurity was less than 25% of the total activity, there was less than a 10% decrease in the therapeutic index. CONCLUSION: The shorter physical half-life of 64Cu relative to that of 67Cu and slower uptake and longer retention of antibody by tumor than by marrow result in a lower therapeutic index for 64Cu. The 25% radioimpurity of 64Cu causes less than 10% deviation in activity quantitation and diminution in the therapeutic index. The change in therapeutic index is predictable over time and can be used to determine the optimal time for radiopharmaceutical administration.

Factors affecting 131I-Lym-1 pharmacokinetics and radiation dosimetry in patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia.

UNLABELLED: Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced therapeutic responses in patients with non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) when labeled with 131I. Responders had statistically significant prolongation of survival compared with nonresponders. The nonmyeloablative, maximum tolerated dose for each of two doses of 131I-Lym-1 was 3.7 GBq/m2 (total 7.4 GBq/m2 [100 mCi/m2, total 200 mCi/m2]) of body surface area. The purpose of this study was to determine the pharmacokinetics and radiation dosimetry for the initial 131I-Lym-1 therapy dose in patients with NHL and CLL and to compare tumor dosimetry with 131I-Lym-1 dosing and other patient parameters. METHODS: Fifty-one patients with stage 3 or 4 lymphoma were treated with 131I-Lym-1 (0.74-8.04 GBq [20-217 mCi]) in either a maximum tolerated dose (MTD) or low-dose (LD) trial. Total Lym-1 given to each patient was sufficient in all instances to exceed the threshold required for stable pharmacokinetics. Quantitative imaging and physical examination, including caliper and CT measurement of tumor size and analysis of blood, urine and feces, were performed for a period of 7 to 10 d after infusion to assess pharmacokinetics and radiation dosimetry. Clinical records were reviewed to obtain data required for comparative assessments. RESULTS: The concentration (%ID/g) and biologic half-time of 131-Lym-1 in tumor were about twice those in normal tissues, although tumor half-time was similar to that of the thyroid. Pharmacokinetics were similar for patients in the MTD and LD trials, and for NHL and CLL patients in the LD trial, except that the latter group had less tumor concentration of 131I. Mean tumor radiation dose per unit of administered 131I was 1.0 Gy/GBq (3.7 rad/mCi) for patients with NHL whether in MTD or LD trials, about nine times greater than that for body or marrow. Tumor radiation dose was less and liver radiation dose was more in patients with CLL. Otherwise, radiation dosimetry was, on average, remarkably similar among groups of patients and among individual patients. Pharmacokinetics and dosimetry did not appear to be influenced by the amount of 131I or Lym-1 within the ranges administered. Tumor concentration of 131I and radiation dose per gigabecquerel were inversely related to tumor size but did not seem to be related to histologic grade or type, tumor burden or therapeutic response. CONCLUSION: The therapeutic index of 131I-Lym-1 was favorable, although the index for patients with CLL was less than that for patients with NHL. Pharmacokinetics and radiation dosimetry were, on average, remarkably similar among patients and groups of patients in different trials.

Prediction of radiation doses from therapy using tracer studies with iodine-131-labeled antibodies.

UNLABELLED: Tracer pharmacokinetic studies are often used in treatment planning for radionuclide therapy including radioimmunotherapy. This study evaluates the validity of using tracer studies to predict radiation doses from therapy with the same radiolabeled antibody. METHODS: Quantitative imaging and blood radioactivity were used to obtain the pharmacokinetics and radiation doses that were delivered to the total body, blood, marrow, lungs, liver, kidneys, thyroid, spleen and tumors. Tracer and therapy data for eight patients with lymphoma and one patient with breast cancer were compared using linear regression statistics. Doses of 131I-labeled antibody for the tracer studies ranged from 0.1 to 0.4 GBq (2 to 10 mCi), and therapy doses ranged from 0.7 to 5.6 GBq (20 to 150 mCi). RESULTS: Radiation doses to tissues and, in particular, the bone marrow and tumors were reliably predicted from tracer studies. In this group of patients, median dose to marrow from marrow targeting, total body and blood was 9.2 cGy/GBq for tracer studies and 7.6 cGy/GBq for therapy studies with a median difference of 0.5 cGy/GBq. Median dose to tumors was 81.1 cGy/GBq for tracer studies and 70.3 cGy/GBq for therapy studies with a median difference of 5.9 cGy/GBq. CONCLUSION: In these patients, tracer studies were predictive of the radiation doses from therapy for total body, major organs and tumors. The radiation doses to marrow and tumors, which are the usual determinants of the therapeutic index, correlated well between tracer and therapy studies (r > or = 0.95).

67Cu-2IT-BAT-Lym-1 pharmacokinetics, radiation dosimetry, toxicity and tumor regression in patients with lymphoma.

UNLABELLED: Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced therapeutic responses and prolonged survival in patients with non-Hodgkin's lymphoma when labeled with 1311. Radiometal-labeled antibodies provide higher tumor radiation doses than corresponding 1311 antibodies. 67Cu has an exceptional combination of properties desirable for radioimmunotherapy, including gamma and beta emissions for imaging and therapy, respectively, a biocompatible half-time and absence of pathways contributing to myelotoxicity. The radioimmunoconjugate, 67Cu-21T-BAT-Lym-1, has been shown to be efficacious in nude mice bearing human Burkitt's lymphoma (Raji) xenografts. Based on these results, a clinical study of the pharmacokinetics and dosimetry of 67Cu-21T-BAT-Lym-1 in patients with lymphoma was initiated. METHODS: Eleven patients with advanced stage 3 or 4 lymphoma were given a preload dose of unmodified Lym-1, then an imaging dose of 126-533 MBq (3.4-14.4 mCi) 67Cu-21T-BAT-Lym-1. Total Lym-1 ranged from 25 to 70 mg dependent on the specific activity of the radioimmunoconjugate and was infused at a rate of 0.5-1 mg/min. Imaging, physical examination, including caliper measurement of superficial tumors, and analysis of blood, urine and fecal samples were performed for a period of 6-13 d after infusion to assess pharmacokinetics, radiation dosimetry, toxicity and tumor regression. RESULTS: In 7 patients, in whom superficial tumors had been accurately measured, tumors regressed from 18% to 75% (mean 48%) within several days of 67Cu-21T-BAT-Lym-1 infusion. The uptake and biological half-time of 67Cu-21T-BAT-Lym-1 in tumors were greater than those of normal tissues, except the mean liver half-time exceeded the mean tumor half-time. The mean tumor-to-marrow radiation ratio was 32:1, tumor-to-total body was 24:1 and tumor-to-liver was 1.5:1. Images were of very good quality; tumors and normal organs were readily identified. Mild and transient Lym-1 toxicity occurred in 6 patients; 1 patient developed a human antimouse antibody. There were no significant changes in blood counts or serum chemistries indicative of radiation toxicity. CONCLUSION: Because of the long residence time of 67Cu-21T-BAT-Lym-1 in tumors, high therapeutic ratios were achieved and, remarkably, numerous tumor regressions were observed after imaging doses. The results indicate considerable therapeutic potential for 67Cu-21T-BAT-Lym-1.

Reproducibility of operator processing for radiation dosimetry.

Reproducibility of operator processing for radiation dose and biological half-life was assessed for radioimmunotherapy. Mean coefficient of variation for intra-operator consecutive processing and for inter-operator processing was less than 15% for all tissues. The mean coefficient of variation for intraoperator processing over 2 wk or inter-operator processing comparing an experienced and less experienced operator was generally greater, and particularly so for tumors. Satisfactory reproducibility was achievable using visual determination of regions of interests after 80 h of training.

Practical determination of organ S values for individual patients for therapy.

Radiation dose calculations using S values of a reference man can introduce substantial errors for individuals patients. We found that all non target sources can be included in the remainder of the body estimate for therapeutic radionuclides. A practical method to derive organ S values based on MIRD data and the mass of the organ and total body of individual patients is proposed.

Radioimmunotherapy for advanced breast cancer using I-131-ChL6 antibody.

BACKGROUND: The biologically active, antiadenocarcinoma monoclonal antibody chimeric L6 (ChL6) was labeled with 131I and administered in cycles to patients with metastatic breast cancer who had failed standard therapy. The therapeutic potential, tumor targeting and maximum tolerated dose of 131I-ChL6 were studied. METHODS: Ten patients with L6 reactive breast cancer received an imaging dose of 131I-ChL6 followed 24 hours later by a therapy dose of 131I-ChL6 (20-70 mCi/m2). Patients received up to 4 monthly cycles unless they had significant myelosuppression, progression of disease, or a high human anti-mouse antibody titer. In vivo activation of effector cell function, complement levels and cytokine release were studied. RESULTS: All 10 patients had detectable cancer on the imaging study. In 7 patients with superficial cancer, the radiation dose was 120 to 3700 cGy/cycle; 5-30 times higher than the whole body dose. Therapy resulted in minimal acute or subacute toxicity. Dose limiting toxicities were neutropenia and thrombocytopenia. Six of 10 patients had clinically measurable tumor responses; 5 had responses that lasted more than one month (1.5-5 months). The MTD for 131I-ChL6, given in at least two monthly doses, was 60 mCi/m2. CONCLUSION: Objective clinical responses were seen in five of 10 patients treated with 131I-ChL6. The tumor response in heavily pretreated, advanced breast cancer may be related to the combined effects of targeted radiation and the biological activity of L6/ChL6.

Maximum tolerated dose of 67Cu-2IT-BAT-LYM-1 for fractionated radioimmunotherapy of non-Hodgkin's lymphoma: a pilot study.

PURPOSE: Lym-1, a monoclonal antibody (MoAb) that preferentially targets malignant lymphocytes, has induced therapeutic responses in patients with non-Hodgkin's lymphoma (NHL) when labeled with iodine-131 (131I). Radiometal labeled antibodies provide a higher tumor radiation dose than the corresponding 131I labeled antibodies. Based on the strategy of fractionating the total radiation dose, this study was designed to define the maximum tolerated dose (MTD) of the first 2, of a maximum of 4, doses of 67Cu-2IT-BAT-Lym-1 given 4 weeks apart. Additionally, toxicity, radiation dosimetry and efficacy were assessed. MATERIALS AND METHODS: Patients had Ann Arbor stage IVB NHL, resistant to standard therapy, including multiple chemotherapy regimens. Each dose of 67Cu-2IT-BAT-Lym-1 was given after a preload of unmodified Lym-1. A 10 mCi imaging dose of 67Cu-2IT-BAT-Lym-1 was given in order to assess pharmacokinetics and radiation dosimetry prior to therapy. Based on the MTD for 131I-Lym-1 and comparative dosimetry for 131I-Lym-1 and 67Cu-2IT-BAT-Lym-1, the trial was initiated at 60 millicuries per square meter of body surface area (mCi/m2) in cohorts of 3 patients. RESULTS: A single cohort of patients proved sufficient to define the MTD as 60 mCi/m2 for each of the first 2 doses of 67Cu-2IT-BAT-Lym-1. The dose-limiting toxicities were grade 3-4 thrombocytopenia and neutropenia. Neutropenic sepsis and bleeding did not occur. Mean radiation dose contributed to the bone marrow by 67Cu in the body and blood was 0.2 (range, 0.2 to 0.3) rads/mCi. Copper-67 incorporated into ceruloplasmin contributed 25% of the dose to marrow from blood. Non-hematologic toxicities did not exceed grade 2. The three patients had substantial tumor regression even after imaging doses of 67Cu-2IT-BAT-Lym-1. After therapy, one response was complete with a duration of 12 months. Radiation doses to tumors in this patient varied from 7.0-21.9 rads/mCi or 5420-7000 total rads from the course of therapy. CONCLUSION: 67Cu-2IT-BAT-Lym-1 provided good imaging, favorable radiation dosimetry and a remarkably high therapeutic index (ratio of tumor to marrow radiation doses). The non-myeloablative MTD for each of 2 doses was 60 mCi/m2.

Radioimmunotherapy of acquired immunodeficiency syndrome (AIDS) associated lymphoma.

Standard therapy for AIDS associated NHL (AANHL) is toxic and often ineffective. Radioimmunotherapy (RIT) is an appealing alternative to chemotherapy because of the radiosensitivity of NHL and the ability of the Lym-1 monoclonal antibody to target therapeutic irradiation to NHL while relatively sparing normal tissue. A Phase I/II study of 90Y-2IT-BAD-Lym-1 was designed specifically for RIT of AANHL. The first patient has been treated with 15 mCi (7.5 mCi/m2) of 90Y-2IT-BAD-Lym-1, after an imaging dose of 111In-2IT-BAD-Lym-1. Before RIT, AANHL in the maxillary sinus extended into the oral cavity and axillary adenopathy was present. Imaging showed excellent accumulation of 111In-2IT-BAD-Lym-1 in the tumors. Substantial shrinkage of the oral lymphoma was observed 18 hours after the therapy dose of 90Y-2IT-BAD-Lym-1 and axillary adenopathy had disappeared by one week after RIT. Transient Grade IV myelosuppression was the only notable toxicity. Further RIT cycles were precluded by development of an antibody response (HAMA) against Lym-1. This novel preliminary study has shown that Lym-1 can target AANHL and produce significant tumor regression thereby providing encouragement to proceed with additional patients.

Estimation of radiation absorbed doses to the red marrow in radioimmunotherapy.

Myelotoxicity is the dose-limiting factor in radioimmunotherapy. Traditional methods most commonly used to estimate the radiation adsorbed dose to the bone marrow of patients consider contributions from radionuclide in the blood and/or total body. Targeted therapies, such as radioimmunotherapy, add a third potential source for radiation to the bone marrow because the radiolabeled targeting molecules can accumulate specifically on malignant target cells infiltrating the bone marrow. A non-invasive method for estimating the radiation absorbed dose to the red marrow of patients who have received radiolabeled monoclonal antibodies (MoAb) has been developed and explored. The method depends on determining the cumulated activity in three contributing sources: 1) marrow; 2) blood; and 3) total body. The novel aspect of this method for estimating marrow radiation dose is derivation of the radiation dose for the entire red marrow from radiation dose estimates obtained by detection of cumulated activity in three lumbar vertebrae using a gamma camera. Contributions to the marrow radiation dose from marrow, blood, and total body cumulated activity were determined for patients who received an I-131 labeled MoAb, Lym-1, that reacts with malignant B-lymphocytes of chronic lymphocytic leukemia and nonHodgkin's lymphoma. Six patients were selected for illustrative purposes because their vertebrae were readily visualized on lumbar images. The radiation doses to the marrow contributed by nonpenetrating emissions in the marrow blood and penetrating emissions in the total body were similar in these patients with a mean of 0.2 and 0.3 rads per administered mCi from the blood and total body, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of splenomegaly on therapeutic response and I-131-LYM-1 dosimetry in patients with B-lymphocytic malignancies.

BACKGROUND: Patients with B-cell non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) frequently have splenomegaly, which has been reported to cause poor tumor targeting of radiolabeled antibodies. Consequently, patients with splenomegaly have been ineligible for some trials of radioimmunotherapy because of the assumption that they would not benefit. METHODS: Forty-nine patients with NHL and five with CLL received an initial dose of 131I-Lym-1 ranging from 740-8140 MBq. Six patients had prior splenectomy. The remaining 48 patients had spleen volumes ranging from 140-2830 ml determined using x-ray computed tomography. Medical Internal Radiation Dose Committee formalism was used to determine dosimetry, and spleen volume was used to adjust the S value for the spleen of each patient. RESULTS: Spleen radiation dose decreased as spleen volume increased, although there was a positive correlation (r = 0.75) between spleen volume and spleen cumulated activity. There was no clear relationship between spleen volume and tumor radiation dose, although tumor radiation doses were low in five patients whose spleen volumes were greater than or equal to 970 ml. There was no apparent relationship between spleen volume and therapeutic response to 131I-Lym-1. Two of five patients whose spleen volumes were greater than or equal to 970 ml responded despite low tumor radiation doses, whereas two of six patients with prior splenectomy did not respond. CONCLUSIONS: The results of this study provide no clear evidence that patients with splenomegaly should be excluded from radioimmunotherapy trials because of the assumption that they will not benefit. Splenomegaly was associated with decreased radiation dose to the spleen, and to tumors only for extraordinarily large spleens.

Imaging for improved prediction of myelotoxicity after radioimmunotherapy.

BACKGROUND: The severity of myelotoxicity after radioimmunotherapy has been predicted from body and blood radiation doses to marrow. However, marrow radiation can be increased substantially if the marrow or skeleton contains the malignancy targeted by the radiolabeled monoclonal antibodies. A study of 29 patients treated with iodine-131 (131I)-Lym-1 showed that radiation doses to marrow from body and blood had little correlation with myelotoxicity. The purpose of the present study was to assess the significance of marrow targeting and other factors for prediction of myelotoxicity. METHODS: Injected radioactivity and nontargeted radiation doses to marrow were compared with peripheral blood cell counts after the first therapy dose of 131I-Lym-1 in 16 heavily pretreated patients with non-Hodgkin's lymphoma (NHL). Bone marrow biopsy, targeted marrow radiation doses, marrow image uptake scores, age, Karnofsky performance score (KPS), previous chemotherapy, and tumor burden were also compared with blood counts. RESULTS: Myelotoxicity was not predicted well by injected radioactivity, total body radiation, or body and blood radiation doses contributed to marrow (P > 0.1). Biopsy-proven bone marrow lymphoma also failed to predict myelotoxicity (P > 0.1). Thrombocytopenia and leukopenia were predicted well by targeted radiation dose to marrow (P < 0.05) obtained by 131I imaging. Similarly, marrow image scores predicted decreases in platelets and white blood cells (WBCs; P < 0.05). Prediction of myelotoxicity using marrow radiation dose methods was slightly improved when serum lactic dehydrogenase (LDH), age, KPS, and prior chemotherapy were included in the analysis (P < or = 0.01). CONCLUSIONS: Prediction of myelotoxicity was improved in this group of patients by assessment of the targeting component of marrow radiation and was better predicted and obtained more easily by semiquantitative marrow image scores. Further improvement in prediction was slight when other factors were considered.

Quantification of iodine-131 in tumors using a threshold based on image contrast.

Accurate and reproducible quantification of tumor radioactivity by imaging requires definition of a region of interest (ROI) for the tumor. The use of a threshold for creating the tumor ROI based on tumor-to-background image contrast (image contrast) was examined. Quantification of iodine-131 in spheres in a phantom that simulated tumors in patients was investigated using planar imaging and geometric-mean and effective-point-source methods. Thresholds that provided the least quantitative error for spheres with different diameters (1-5 cm) and locations (0-11 cm deep in the body), 131I concentrations (0.037-3.2 MBq/ml), and sphere-to-background concentration ratios (1:0, 14:1 and 7:1) were investigated. The correlation between threshold and sphere image contrast was examined. The phantom study showed that an appropriate threshold value for quantification of tumor radioactivity could be determined using image contrast for a single view, provided that image contrast was >/=1.5. The error of quantification was less than 10% for spheres with high image contrast (>/=1.5) but was greater than 17% for spheres with low image contrast (<1.5). When image contrast-dependent thresholds were applied to patient studies, 131I concentrations determined by imaging were in good agreement with the concentrations determined by counting biopsy samples. Additionally, reproducibility was improved when compared with a visual boundary method. It is concluded that accurate and reproducible quantification of radioactivity in tumors is achievable using thresholds based on image contrast if image contrast is greater than or equal to 1.5. Optimal thresholds for quantification of tumor radioactivity were similar if image contrast was similar despite differing tumor diameters, locations and 131I concentrations. Under certain circumstances, the effective-point-source method was preferable to the geometric-mean method.