Biodistribution and localization of iodine-131-labeled metuximab in patients with hepatocellular carcinoma

PURPOSE: Radioimmunotherapy may improve the outcome of hepatocellular carcinoma (HCC) patients by delivering targeted radiation to liver lesion tissue while relatively sparing nontarget tissues. This study was designed to observe the biodistribution, localization and imaging characteristics of 131I -labeled Metuximab in 24 patients with HCC to determine the diagnostic and therapeutic potential of this antibody. METHODS: Twenty-four HCC patients were randomly divided into three groups to receive 18.5, 27.75 and 37 MBq/kg of 131I-labeled Metuximab per kilogram of body weight, respectively. 99mTc-sodium phytate was administered intravenously and the single photon emission computed tomography (SPECT) scanning was performed. After 48 h, 131I -labeled Metuximab was injected by hepatic artery intubation, and SPECT scan performed at 7 d. The percentage of absorbed 131I (%ID) and the time-dependent 131I tumor:nontumor tissue (T/NT) ratios were calculated at 12, 48, 96 and 192 h after injection. RESULTS: The positive Imaging result of MAb scanning in 24 patients showed that the iodine 131 conjugated to Metuximab was apparently accumulated more in hepatoma. Biodistribution studies of 131I-Metuximab in trial I demonstrated that the comparable % ID uptake in tumor (with a T/NT ratio at 12, 48, 96 and 192 h) to that in such normal organs, as thyroid, heart, lung, spleen and intestines were all more than one. The optimal imaging time for the highest T/NT ratio in liver was at 192 h. CONCLUSION: 131I-labeled Metuximab could deliver relatively selective radiation to tumor tissues and may have potential efficacy in relieving hepatocellular carcinoma.     

Repeat treatment with iodine-131-rituximab is safe and effective in patients with relapsed indolent B-cell non-Hodgkin's lymphoma who had previously responded to iodine-131-rituximab

BackgroundSmall series suggest retreatment of indolent lymphomas with murine anti-CD20 radioimmunotherapy is effective. The longer half-life of iodine-131 (¹³¹I)-rituximab may result in increased bone marrow exposure, with greater toxicity on repeat administration. We examined the effects of a second ¹³¹I-rituximab in patients with indolent lymphoma following relapse.Patients and methodsWe analyzed two institutional databases from January 2000 to July 2007 for retreatment with ¹³¹I-rituximab. The severity of cytopenia, development of myelodysplasia (MDS), acute myeloid leukemia (AML) and hypothyroidism was noted. We compared response duration and toxicity of the treatments.ResultsFourteen of 16 patients responded with nine complete responses (CRs), with a median duration of 10.5 months in responders. Six of 13 reresponders had the same or a longer response and six more remain in complete response. The median event-free survival was not significantly different for the two treatments. There was no significant difference in the severity of myelosuppression. Four patients developed hypothyroidism with three requiring thyroxine. One patient developed AML, with no other cases of MDS. The actuarial progression-free survival rate at 12 months was 36%.ConclusionsRepeat ¹³¹I-rituximab induces high response rates, some of which result in durable remissions in patients who had previously responded.     

Leukaemias and cancers following iodine-131 administration for thyroid cancer.

We studied 1771 patients treated for a thyroid cancer in two institutions. None of these patients had been treated with external radiotherapy and 1497 had received (131)I. The average (131)I cumulative activity administered was 7.2 GBq, and the estimated average dose was 0.34 Sv to the bone marrow and 0.80 Sv to the whole body. After a mean follow-up of 10 years, no case of leukaemia was observed, compared with 2.5 expected according to the coefficients derived from Japanese atomic bomb survivors (P = 0.1). A total of 80 patients developed a solid second malignant neoplasm (SMN), among whom 13 developed a colorectal cancer. The risk of colorectal cancer was found to be related to the total activity of (131)I administered 5 years or more before its diagnosis (excess relative risk = 0.5 per GBq, P = 0.02). These findings were probably caused by the accumulation of (131)I in the colon lumen. Hence, in the absence of laxative treatment, the dose to the colon as a result of (131)I administered for the treatment of thyroid cancer could be higher than expected from calculation of the International Commission on Radiological Protection (ICRP). When digestive tract cancers were excluded, the overall excess relative risk of second cancer per estimated effective sievert received to the whole body was -0.2 (P = 0.6).     

Comparative physical and pharmacologic characteristics of iodine-131 and yttrium-90: implications for radioimmunotherapy for patients with non-Hodgkin's lymphoma

Radioimmunotherapy (RIT) is a promising new treatment option for patients with relapsed/refractory non-Hodgkin's lymphoma. Clinical trials have demonstrated that both iodine-131 (¹³¹I) and yttrium-90 (⁹⁰Y) are suitable radionuclides for RIT. Iodine-131 and ⁹⁰Y differ markedly in their physical properties including half-life, path length, type of energy emissions, intracellular stability, and the organs targeted by the free radionuclide. Both radionuclides can be safely administered in the outpatient setting under current Nuclear Regulatory Commission guidelines. Potential advantages of ¹³¹I for RIT include availability, stable chemistry, longer half-life, and an emission spectrum that allows for dosimetric studies and therapy with the same immunoconjugate. By contrast, ⁹⁰Y has a longer path length and superior intracellular stability compared with ¹³¹I. Yttrium-90 may therefore be preferable to ¹³¹I for patients with bulky disease, poorly vascularized solid tumors, or when targeting internalized antigens. Although ⁹⁰Y emits no gamma photon, dosimetry studies for ⁹⁰Y RIT can be performed using a surrogate radionuclide such as indium-111. Both ¹³¹I- and ⁹⁰Y-labeled anti-CD20 antibodies have demonstrated efficacy in treating relapsed/refractory non-Hodgkin's lymphoma. Further studies are needed, however, to determine if the differences in the pharmacology of ¹³¹I and ⁹⁰Y are clinically relevant.     

Incorporating leaf transmission and head scatter corrections into step-and-shoot leaf sequences for IMRT

PURPOSE: Leaf transmission and head scatter are two important factors that influence intensity-modulated radiation therapy (IMRT) delivery and should be correctly taken into account when generating multileaf collimator (MLC) sequences. Significant discrepancies between the desired and delivered intensity profiles could otherwise result. The purpose of this article is to propose a reliable algorithm to minimize the dosimetric effects caused by the two factors in step-and-shoot mode. MATERIALS AND METHODS: The goal of the algorithm is to minimize the difference between the desired fluence map and the fluence map actually delivered. For this purpose, an error function, defined as the least-square difference between the desired and the delivered fluence maps, is introduced. The effects of transmission and head scatter are minimized by adjusting the fractional monitor units (MUs) in the initial MLC sequences, created by using the desired fluence map without inclusion of the contributions from the two factors. Computationally, a downhill simplex optimization method is used to minimize the error function with respect to the fractional MUs. A three-source model is used to evaluate the relative head scatter distribution for each segment at the beginning of the calculation. The algorithm has been assessed by comparing the dose distributions delivered by the corrected leaf sequence files and the theoretic predication, calculated by Monte Carlo simulation using the desired fluence maps, for an intuitive test field and several clinical IMRT cases. RESULTS: The deviations between the desired fluence maps and those calculated using the corrected leaf sequence files are <0.3% of the maximum MU for the test field and <1.0% for the clinical IMRT cases. The experimental data show that both absolute and relative dose distributions delivered by the corrected leaf sequences agree with the desired ones within 2.5% of the maximum dose or 2 mm in high-dose gradient regions. Compared with the results obtained by using the leaf sequences in which only the transmission or none of the two effects is corrected, significant improvements in the fluence and dose distributions have been observed. CONCLUSIONS: Transmission and head scatter play important roles in the dosimetric behavior of IMRT delivery. A larger error may result if only one factor is considered because of the opposite effects of the two factors. We noted that the influence of the two effects is more pronounced in absolute dose than in the relative dose. The algorithm proposed in this work accurately corrects for these two effects in step-and-shoot delivery and provides a reliable tool for clinical IMRT application.     

Hematologic toxicity of high-dose iodine-131-metaiodobenzylguanidine therapy for advanced neuroblastoma.

PURPOSE: Iodine-131-metaiodobenzylguanidine ((131)I-MIBG) has been shown to be active against refractory neuroblastoma. The primary toxicity of (131)I-MIBG is myelosuppression, which might necessitate autologous hematopoietic stem-cell transplantation (AHSCT). The goal of this study was to determine risk factors for myelosuppression and the need for AHSCT after (131)I-MIBG treatment. PATIENTS AND METHODS: Fifty-three patients with refractory or relapsed neuroblastoma were treated with 18 mCi/kg (131)I-MIBG on a phase I/II protocol. The median whole-body radiation dose was 2.92 Gy. RESULTS: Almost all patients required at least one platelet (96%) or red cell (91%) transfusion and most patients (79%) developed neutropenia (< 0.5 x 10(3)/microL). Patients reached platelet nadir earlier than neutrophil nadir (P <.0001). Earlier platelet nadir correlated with bone marrow tumor, more extensive bone involvement, higher whole-body radiation dose, and longer time from diagnosis to (131)I-MIBG therapy (P 相似文献   

Intra-arterial injection of iodine-131-labeled lipiodol for treatment of hepatocellular carcinoma.

BACKGROUND/AIM: The therapeutic effect of intra-arterial injection of 131-iodine-labeled lipiodol for treatment of hepatocellular carcinoma in palliative or adjuvant settings has been promising. We report, the results of an open study of this therapy in cirrhotic patients with small hepatocellular carcinoma. PATIENTS AND METHOD: Forty patients with hepatocellular carcinoma were given intra-arterial injections of 131-iodine-labeled lipiodol. These injections were repeated if necessary every 3 months. Tumor response (WHO criteria) was determined on CT scans performed after each treatment and every 3 months during the follow-up. Side effects and the cause of death were recorded. Therapeutic response and survival were analyzed. RESULTS: The median number of treatment was 2 (1-4). There was one complete response, 18 partial responses (47.5% response rate); 19 had stable disease and 2 progressions. Overall survival rates (+/-CI 95%) at 1, 2 and 3 years were: 90+/-4.7%, 60.3+/-8%, and 39+/-8.3%, respectively. Median survival was 27 months; 25 patients have died (4-56 months), 8 of tumor progression with a multifocal spread in the liver. Tolerance was good except for 2 patients who develop a fatal drug-related pulmonary insufficiency. CONCLUSION: These data suggest that intra-arterial therapeutic injection of 131-iodine-labeled lipiodol for treatment of hepatocellular carcinoma can provide high rate response and long survival for individuals not eligible for surgery or local treatment.     

An overview of attenuation and scatter correction of planar and SPECT data for dosimetry studies

A number of factors impact the accuracy of activity quantitation in planar and single photon emission computed tomographic (SPECT) imaging. Two important such factors are attenuation and scattering in the medium containing the activity. The first removes photons which otherwise would have been included in the images, and the second adds events to the images from photons which would not have otherwise been imaged. A number of methods have been developed to compensate for these biases to activity quantitation. This review will briefly introduce planar quantitation which is commonly used for dosimetric purposes, and then present a slightly more detailed overview of SPECT quantitation which is arguably more accurate. It will conclude by cautioning users of commercial reconstruction software to validate it for quantitation before using it for dosimetric purposes.     

Yttrium-90 and iodine-131 radioimmunoglobulin therapy of an experimental human hepatoma

Therapeutic trials were performed on the HepG2 human hepatoblastoma implanted s.c. in the athymic nude mouse. Animals were treated with polyclonal and monoclonal antiferritin and control antibodies labeled with either iodine-131 (131I) or yttrium-90 (90Y). Administration of 400 muCi of 131I-labeled polyclonal antiferritin or 300 muCi of 90Y-labeled polyclonal antiferritin significantly increased survival (P less than 0.001). There were no tumor cures with radiolabeled polyclonal antibody therapy. Animals treated with 200 or 300 muCi of 131I-labeled monoclonal antiferritin (QCI054) did not show increased survival compared to controls. Although 400 muCi of 131I-labeled QCI significantly prolonged survival, treatment resulted in no long-term survivors. Monoclonal antiferritin labeled with 90Y significantly prolonged survival of animals (P less than 0.001) at doses of 100, 200, or 300 muCi compared with untreated controls. Fifty % of the animals treated with 200 muCi and 75% of the animals treated with 300 muCi showed no evidence of disease at 140 days following treatment. Four hundred muCi of 90Y-labeled QCI proved toxic to the animals. Increased survival was accompanied by a decrease in tumor mitotic rate and increase in cellular polymorphism as determined by pathological examination. The radiation dose absorbed in the tumor correlated directly with tumor response following treatment. The absorbed dose in tumors for complete decay of the isotope ranged from 165 and 330 cGy at the periphery and center of small tumors for an administered activity of 200 muCi of 131I-labeled polyclonal antiferritin, to 7,573 and 12,400 cGy for 300 muCi of 90Y-labeled monoclonal antiferritin QCI.     

Optimization of energy-window settings for scatter correction in quantitative (111)In imaging: comparison of measurements and Monte Carlo simulations

Activity quantification in nuclear medicine imaging is highly desirable, particularly for dosimetry and biodistribution studies of radiopharmaceuticals. Quantitative (111)In imaging is increasingly important with the current interest in therapy using (90)Y radiolabeled antibodies. One of the major problems in quantification is scatter in the images, which leads to degradation of image quality. The aim of this study was to optimize the energy-window settings for quantitative (111)In imaging with a camera that enabled acquisition in three energy windows. Experimental measurements and Monte Carlo simulations, using the SI-MIND code, were conducted to investigate parameters such as sensitivity, image contrast, and image resolution. Estimated scatter-to-total ratios and distributions, as obtained by the different window settings, were compared with corresponding simulations. Results showed positive agreement between experimental measurements and results from simulations, both quantitatively and qualitatively. We conclude that of the investigated methods, the optimal energy-window setting was two windows centered at 171 and 245 keV, together with a broad scatter window located between the photopeaks.     

Pivotal study of iodine-131-labeled chimeric tumor necrosis treatment radioimmunotherapy in patients with advanced lung cancer.

PURPOSE: Tumor necrosis treatment (TNT) uses degenerating tumor cells and necrotic regions of tumors as targets for radioimmunotherapy. Previous studies in animal tumor models and clinical trials have demonstrated that when linked to the therapeutic radionuclide iodine-131, recombinant chimeric TNT antibody ((131)I-chTNT) can deliver therapeutic doses to tumors regardless of the location or type of malignancy. Therapeutic efficacy and toxicity of (131)I-chTNT in advanced lung cancer patients were studied in this pivotal registration trial. PATIENTS AND METHODS: Patients with advanced lung cancer were treated with systemic or intratumoral injection of (131)I-chTNT in eight oncology centers in China. The objective response rate (ORR) was assessed as the primary end point. RESULTS: All 107 patients who were entered onto the study and completed therapy had experienced treatment failure after prior radiotherapy or chemotherapy a mean of three times. The results showed an ORR of 34.6% (complete response, 3.7%; partial response, 30.8%; no change, 55.1%; and progressive disease, 10.3%) in all patients and 33% in 97 non-small-cell lung cancer patients. A biodistribution study demonstrated excellent localization of the radioactivity in tumors in both systemically and intratumorally injected patients. The most obvious adverse side effect was mild and reversible bone marrow suppression. CONCLUSION: Radioimmunotherapy with (131)I-chTNT was well tolerated and can be used systemically or locally to treat refractory tumors of the lung.     

Synergistic cytotoxicity of iodine-131-anti-CD20 monoclonal antibodies and chemotherapy for treatment of B-cell lymphomas

Preliminary clinical trials suggest that iodine-131 ((131)I)-labeled anti-CD20 monoclonal antibodies (MAbs) are effective single agents for the treatment of relapsed non-Hodgkin's B-cell lymphomas. However, despite high initial response rates, most patients treated in this manner will eventually relapse. We hypothesized that regimens combining (131)I-anti-CD20 antibodies with standard chemotherapeutic agents may provide synergistic anti-tumor effects, and may improve the durability of responses in patients with lymphoma. To identify promising agents for clinical testing, we assessed the in vitro cytotoxicity of combinations of (131)I-anti-B1 (anti-CD20) antibody and 8 chemotherapeutic agents using 2 human CD20-expressing lymphoma cell lines and 2 corroborative assays, the thiazolyl tetrazolium bromide (MTT) and the Trypan blue dye exclusion assays. ID(50) isobolographic and dose modification factor (DMF) analyses were used to classify interactions between the (131)I-anti-B1 antibody and the chemotherapeutic agents as supra-additive (synergistic), additive or sub-additive. Cytarabine and fludarabine were markedly supra-additive when combined with the radioimmunoconjugate, with the combination enhancing cytotoxicity 3. 5- to 5.2-fold over the level expected by simple addition of the 2 agents (DMFs 3.5-5.2). Etoposide, doxorubicin and SN-38 were moderately supra-additive (DMFs 2.0-2.8). Cisplatin and 4-hydroxycyclophosphamide exhibited merely additive cytotoxicity (DMFs 1.0-1.1). Thus, combination regimens containing (131)I-labeled anti-CD20 antibodies and nucleoside analogs or topoisomerase inhibitors appear particularly attractive for future clinical trials.     

Treatment of refractory Hodgkin's lymphoma patients with an iodine-131-labeled murine anti-CD30 monoclonal antibody.

PURPOSE: Hodgkin's lymphoma (HL) has been demonstrated to be a good target for immunotherapy since lymphocyte activation markers such as CD30 are expressed in high numbers on the malignant cells. Thus, we developed a new radioimmunoconjugate consisting of the murine anti-CD30 monoclonal antibody (MAb) Ki-4 labeled with iodine-131 ((131)I). PATIENTS AND METHODS: The biodistribution of (131)I-Ki-4 was assessed via dosimetry after preinfusion of 5 mg native Ki-4 followed by 250 to 300 MBq (131)I-labeled Ki-4. Whole-body scintigraphy was performed 1 hour, 24 hours, 48 hours, 72 hours, and 6 days after the infusion. Dosimetry was calculated using the programs NucliDose ICON-IDL (version 5.0.2; Siemens, Erlanger, Germany) and MIRDOSE (version 3.1; Oak Ridge National Laboratories; Oak Ridge, TN). The therapeutic dose was given on day 8 after preinfusion of unlabeled Ki-4. RESULTS: We treated 22 patients with relapsed or refractory CD30-positive HL. Preinfusion of 5 mg native Ki-4 was sufficient to bind the soluble CD30. Imaging demonstrated localization of involved areas measuring 5 cm in diameter or more in four patients and 2.5 cm in one patient. Patients received total body doses of 0.035 Gy to 0.99 Gy. Acute toxicity was mild with grade 1 fatigue in 19 of 22 assessable patients. Seven patients experienced grade 4 degrees hematotoxicity 4 to 8 weeks after treatment. Response included one complete remission, five partial remissions, and three minor responses. CONCLUSION: Treatment with (131)I-Ki-4 is effective but can be associated with severe hematotoxicity.     

Possible transient adaptive response to mitomycin C in peripheral lymphocytes from thyroid cancer patients after iodine-131 therapy

Our study attempted to assess the possible induction and persistence of an adaptive response in lymphocytes of thyroidectomized thyroid cancer patients treated with 131I (2,590 MBq, corresponding to whole body doses in the range of 200-300 mGy), to a testing dose of mitomycin C (MMC) in vitro. The cytogenetic endpoint studied was the induction of micronuclei in cytokinesis-blocked peripheral blood lymphocytes, immediately before treatment and 1, 6 and 24 months after therapy. One month after therapy, induction of micronucleated cytokinesis-blocked lymphocytes ( per thousand ) by MMC was lower (34.6 +/- 7.7) than before therapy (52.1 +/- 5.0). In 7 of 11 patients this reduction was significant. However, at 6 months, induction of micronuclei was markedly higher (133.1 +/- 13.6). This significant increase was observed regardless of the decrease at 1 month. At 24 months, the frequency of micronucleated cells decreased (84.8 +/- 5.5), but remained higher than before treatment. The results obtained 1 month after therapy could reflect adaptation due to radiation, or a higher rate of early apoptosis or cell death, with bone marrow suppression, visible as a lower response in vitro towards MMC. At 6 months, recovery of the lymphocyte population may occur, and higher responses to MMC in vitro could reflect higher chromosomal instability in the previously irradiated stem cells with a concomitant disappearance of adaptation, whereas at 24 months the results show a tendency to return to pretherapy values.     

Hepatic arterial iodine-131-labeled metuximab injection combined with chemoembolization for unresectable hepatocellular carcinoma: interim safety and survival data from 110 patients

Few options are available to treat patients with hepatocellular carcinoma (HCC). It was tested whether the combination of iodine-131(131I)-metuximab with chemoembolization could improve outcomes in patients with intermediate HCC. Between April 2008 and April 2009, 110 patients with unresectable HCC were treated with 113 intra-arterial 131I-metuximab injections combined with chemoembolization (mean, 1.03 per patient; median, 1; range, 1-2), followed by 264 sessions of transcatheter arterial chemoembolization (mean, 2.4 per patient; median, 3; range, 1-6). The survival rates at 6, 12, and 18 months were 88.2%, 79.1%, and 57.4%, respectively, by the Kaplan-Meier method. Of these patients, 12% exhibited grade 3/4 bilirubin toxicity, 5% exhibited grade 3/4 white blood count toxicity, and 7% exhibited grade 3/4 platelet toxicity. Response rates based on World Health Organization and European Association for the Study of the Liver criteria were 42.73% and 61.82%, respectively. The combination of 131I-metuximab and chemoembolization appeared to extend survival in patients with unresectable HCC compared with historical controls, as well as being well tolerated by patients with Child-Pugh A and B. This combination may represent a promising treatment modality for patients with intermediate HCC.     

Dual energy CT attenuation correction methods for quantitative assessment of response to cancer therapy with PET/CT imaging

We hypothesize that improved quantification for PET imaging of high atomic number materials can be achieved by combining low-dose x-ray imaging with dual energy CT for PET attenuation correction. Improved quantification of tracer uptake will lead to improved patient outcomes by providing more accurate information for therapeutic choices. Accurate PET/CT measurements of early response will be critical in determining the best cancer therapy option for each patient in a timely manner and in sparing patients the morbidity and cost of ineffective treatments. We first evaluate the potential errors in PET images arising from CT-based attenuation correction when iodine-based contrast is incorrectly classified as bone when forming the linear attenuation coefficient image. We then investigate two methods of reducing errors in the linear attenuation image: an approximate, but fast, hybrid classification/scaling algorithm and a model-based dual-energy CT method that incorporates the polyenergetic spectrum and a noise model in an iterative reconstruction method. Both methods are shown to reduce errors in the estimated linear attenuation coefficient image, but require further study to determine the effects of noise propagation if low-dose CT scans are used for the estimation of the linear attenuation image.     

Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin's lymphomas.

PURPOSE: This study is an integrated efficacy analysis of the five clinical trials of tositumomab and iodine-131 tositumomab in patients with relapsed or refractory low-grade, follicular, or transformed low-grade non-Hodgkin's lymphoma (NHL) that resulted in the regulatory approval of the iodine-131 tositumomab by the US Food and Drug Administration. PATIENTS AND METHODS: This integrated analysis included 250 patients. Patients received a single course of iodine-131 tositumomab. Responses were assessed by an independent panel of radiologists and oncologists. RESULTS: Response rates in the five trials ranged from 47% to 68%; complete response rates ranged from 20% to 38%. With a median follow-up of 5.3 years, the 5-year progression-free survival was 17%. Eighty-one (32%) of 250 patients had a time to progression of > or = 1 year (termed durable response population). For the durable response population, 44% had not progressed at > or = 2.5 to > or = 9.5 years and had a median duration of response of 45.8 months. The median duration of complete response was not reached. The durable response population had many poor prognostic characteristics, including bone marrow involvement (41%), bulky disease > or = 5 cm (49%), and transformed histology (23%). Forty-three percent of the patients had been treated with more than four prior therapies and 36% had not responded to their most recent therapy. CONCLUSION: The tositumomab and iodine-131 tositumomab therapeutic regimen produces high response rates in patients with relapsed or refractory low-grade, follicular, and transformed low-grade NHL, with a sizable subgroup of patients achieving long-term durable responses.