Efficient bone marrow irradiation and low uptake by non-haematological organs with an yttrium-90-anti-CD66 antibody prior to haematopoietic stem cell transplantation.

We report the results of a Phase I radiation dose escalation study using an yttrium-90 (90Y) labelled anti-CD66 monoclonal antibody given with standard conditioning regimen for patients receiving haematopoietic stem cell transplants for myeloid leukaemia or myeloma. The 90Y-labelled anti-CD66 was infused prior to standard conditioning. In total, 30 patients entered the trial and 29 received 90Y-labelled mAb, at infused radiation activity levels of 5, 10, 25, or 37.5 megaBequerel (MBq)/kg lean body weight. A prerequisite for receiving the 90Y-labelled mAb was favourable dosimetry determined by single-photon emission computerised tomography (SPECT) dosimetry following administration of indium-111 (111In) anti-CD66. Estimated absorbed radiation doses delivered to the red marrow demonstrated a linear relationship with the infused activity of 90Y-labelled mAb. At the highest activity level of 37.5 MBq/kg, mean estimated radiation doses for red marrow, liver, spleen, kidneys and lungs were 24.6 ± 5.6 Gy, 5.8 ± 2.7 Gy, 19.1 ± 8.0 Gy, 2.1 ± 1.1 and 2.2 ± 0.9, respectively. All patients engrafted, treatment-related mortality 1-year post-transplant was zero. Toxicities were no greater than those anticipated for similar conditioning regimens without targeted radiation. The ability to substantially intensify conditioning prior to haematopoietic stem cell transplantation without increasing toxicity warrants further testing to determine efficacy. clinicaltrials.gov identifier: NCT01521611.

Imaging and therapy in prostate cancer using PSMA radioligands.

Prostate specific membrane antigen (PSMA)-directed PET imaging has rapidly transformed prostate cancer workup over the past decade and paved the way for a theranostic approach using 177Lu-labelled PSMA radioligand therapy. This review gives an overview of the underlying principles behind PSMA as a target; the current use of PSMA PET in prostate cancer imaging and benefits compared to conventional imaging; and therapeutic applications including optimisation of patient selection. It also explores the evidence base of PSMA PET for other indications not in routine clinical use and the future of PSMA-directed radioligand therapy.

Efficacy and safety of 177Lu­DOTATATE in patients with advanced pancreatic neuroendocrine tumours: data from the NETTER-R international, retrospective study.

PURPOSE: NETTER-R aimed to determine the efficacy, safety and tolerability of 177Lu-DOTATATE in patients with progressive, advanced pancreatic neuroendocrine tumours (panNETs) using retrospective real-world data from multiple sites. METHODS: This international study retrospectively included patients with panNETs treated with 177Lu-DOTATATE. The primary endpoint was progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included overall survival (OS), safety and tumour response. RESULTS: In total, 110 patients with panNETs were studied; 65.5% received a cumulative dose of 177Lu-DOTATATE 29.6 GBq ± 10% (median: 7.4 GBq). In 62 patients with available RECIST v1.1 tumour response, the median PFS was 24.8 months (95% confidence interval [CI]: 17.5-34.5), and the objective response rate was 40.3% (95% CI: 28.1-53.6); all responses were partial. With a median follow up of 24.5 months (range: 2.0-123.4 months) after the first cycle of 177Lu-DOTATATE, the median OS in the full analysis set (n = 110) was 41.4 months (95% CI: 28.6-50.2). PFS (hazard ratio [HR]: 3.672; p = 0.0009) and OS (HR: 3.360; p < 0.0001) were longer in patients who received no chemotherapy prior to 177Lu-DOTATATE than those who did. No treatment-emergent adverse events (TEAEs) led to treatment discontinuation. Grade 3 anaemia, lymphopenia and thrombocytopenia occurred in 0.9%, 5.4% and 0.9% of patients, respectively. No acute leukaemia or myelodysplastic syndrome was reported. Six patients (5.5%) had renal TEAEs. All renal grade ≥ 3 events were transient and did not lead to treatment modification. CONCLUSIONS: These results reinforce the role of 177Lu-DOTATATE for the treatment of patients with advanced, somatostatin receptor-positive panNETs.

In vitro cytotoxicity of Auger electron-emitting [67Ga]Ga-trastuzumab.

INTRODUCTION: Molecular radiotherapy exploiting short-range Auger electron-emitting radionuclides has potential for targeted cancer treatment and, in particular, is an attractive option for managing micrometastatic disease. Here, an approach using chelator-trastuzumab conjugates to target radioactivity to breast cancer cells was evaluated as a proof-of-concept to assess the suitability of 67Ga as a therapeutic radionuclide. METHODS: THP-trastuzumab and DOTA-trastuzumab were synthesised and radiolabelled with Auger electron-emitters 67Ga and 111In, respectively. Radiopharmaceuticals were tested for HER2-specific binding and internalisation, and their effects on viability (dye exclusion) and clonogenicity of HER2-positive HCC1954 and HER2-negative MDA-MB-231 cell lines was measured. Labelled cell populations were studied by microautoradiography. RESULTS: Labelling efficiencies for [67Ga]Ga-THP-trastuzumab and [111In]In-DOTA-trastuzumab were 90% and 98%, respectively, giving specific activities 0.52 ± 0.16 and 0.61 ± 0.11 MBq/µg (78-92 GBq/µmol). At 4 nM total antibody concentration and 200 × 103 cells/mL, [67Ga]Ga-THP-trastuzumab showed higher percentage of cell association (10.7 ± 1.3%) than [111In]In-DOTA-trastuzumab (6.2 ± 1.6%; p = 0.01). The proportion of bound activity that was internalised did not differ significantly for the two tracers (62.1 ± 1.4% and 60.8 ± 15.5%, respectively). At 100 nM, percentage cell binding of both radiopharmaceuticals was greatly reduced compared to 4 nM and did not differ significantly between the two (1.2 ± 1.0% [67Ga]Ga-THP-trastuzumab and 0.8 ± 0.9% for [111In]In-DOTA-trastuzumab). Viability and clonogenicity of HER2-positive cells decreased when each radionuclide was incorporated into cells by conjugation with trastuzumab, but not when the same level of radioactivity was confined to the medium by omitting the antibody conjugation, suggesting that 67Ga needs to be cell-bound or internalised for a therapeutic effect. Microautoradiography showed that radioactivity bound to individual cells varied considerably within the population. CONCLUSIONS: [67Ga]Ga-THP-trastuzumab reduced cell viability and clonogenicity only when cell-bound, suggesting 67Ga holds promise as a therapeutic radionuclide as part of a targeted radiopharmaceutical. The causes and consequences of non-homogeneous uptake among the cell population should be explored.

Imaging Features of Succinate Dehydrogenase-deficient Pheochromocytoma-Paraganglioma Syndromes.

Pheochromocytoma (PC) and paraganglioma (PGL) are rare neuroendocrine tumors that occur throughout the body from the base of the skull to the pelvis. Sympathetic catecholamine-secreting tumors may be associated with hyperadrenergic symptoms and long-term morbidity if they are untreated. Typically biochemically silent, head and neck PGLs may result in cranial nerve palsies and symptoms due to localized mass effect. Tumors can arise sporadically or as part of an inheritable PC-PGL syndrome. Up to 40% of tumors are recognized to be associated with germline mutations in an increasing array of susceptibility genes, including those that appear to arise sporadically. Most commonly, up to 25% of all PC-PGLs are associated with mutations in one of the succinate dehydrogenase (SDH) enzyme subunit genes. The resulting familial PC-PGL syndrome varies according to the affected enzyme subunit (most commonly SDHB and SDHD mutations) with respect to tumor prevalence, location, age of onset, and risk of malignancy. Patients with SDH enzyme mutations have increased lifetime risk of developing multifocal tumors and malignancy. Early recognition of individuals at high risk, genetic testing, screening of family members, and lifelong surveillance programs are recommended, but not without health, economic, and psychologic implications. Anatomic and functional imaging is key to diagnosis, staging, treatment planning, and lifelong surveillance of these individuals. Radiologists must be aware of the imaging appearance of these varied tumors.©RSNA, 2019.

Targeted Alpha Therapy, an Emerging Class of Cancer Agents: A Review.

Importance: Targeted alpha therapy attempts to deliver systemic radiation selectively to cancer cells while minimizing systemic toxic effects and may lead to additional treatment options for many cancer types. Observations: Theoretically, the high-energy emission of short-range alpha particles causes complex double-stranded DNA breaks, eliciting cell death. No known resistance mechanism to alpha particles has been reported or scientifically established. The short-range emission of alpha particle radiation confines its cytotoxic effect to cancerous lesions and the surrounding tumor microenvironment while limiting toxic effects to noncancerous tissues. The high level of radiobiological effectiveness of alpha particles, in comparison with beta emissions, requires fewer particle tracks to induce cell death. Clinically effective alpha particle-emitting isotopes for cancer therapy should have a short half-life, which will limit long-term radiation exposure and allow for the production, preparation, and administration of these isotopes for clinical use and application. Radium 223 dichloride is the first-in-class, commercially available targeted alpha therapy approved for the treatment of patients with metastatic castration-resistant prostate cancer with bone metastases. Given the established overall survival benefit conferred by radium 223 for patients with metastatic castration-resistant prostate cancer, several other targeted alpha therapies are being investigated in clinical trials across many tumor types. Conclusions and Relevance: Targeted alpha therapy represents an emerging treatment approach and provides for the possibility to bypass mechanisms of acquired resistance in selected tumors. In addition, developing novel radionuclide conjugation strategies may overcome targeting limitations. So far, the clinical success of radium 223 has demonstrated the proof of concept for targeted alpha therapy, and future studies may lead to additional treatment options for many cancer types.

Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 trials.

BACKGROUND: Validation of the prognostic value of the SIOPEN mIBG skeletal scoring system in two independent stage 4, mIBG avid, high-risk neuroblastoma populations. RESULTS: The semi-quantitative SIOPEN score evaluates skeletal meta-iodobenzylguanidine (mIBG) uptake on a 0-6 scale in 12 anatomical regions. Evaluable mIBG scans from 216 COG-A3973 and 341 SIOPEN/HR-NBL1 trial patients were reviewed pre- and post-induction chemotherapy. The prognostic value of skeletal scores for 5-year event free survival (5 yr.-EFS) was tested in the source and validation cohorts. At diagnosis, both cohorts showed a gradual non-linear increase in risk with cumulative scores. Several approaches were explored to test the relationship between score and EFS. Ultimately, a cutoff score of ≤3 was the most useful predictor across trials. A SIOPEN score ≤ 3 pre-induction was found in 15% SIOPEN patients and in 22% of COG patients and increased post-induction to 60% in SIOPEN patients and to 73% in COG patients. Baseline 5 yr.-EFS rates in the SIOPEN/HR-NBL1 cohort for scores ≤3 were 47% ± 7% versus 26% ± 3% for higher scores at diagnosis (p < 0.007) and 36% ± 4% versus 14% ± 4% (p < 0.001) for scores obtained post-induction. The COG-A3973 showed 5 yr.-EFS rates for scores ≤3 of 51% ± 7% versus 34% ± 4% for higher scores (p < 0.001) at diagnosis and 43% ± 5% versus 16% ± 6% (p = 0.004) for post-induction scores. Hazard ratios (HR) significantly favoured patients with scores ≤3 after adjustment for age and MYCN-amplification. Optimal outcomes were recorded in patients who achieved complete skeletal response. CONCLUSIONS: Validation in two independent cohorts confirms the prognostic value of the SIOPEN skeletal score. In particular, patients with an absolute SIOPEN score > 3 after induction have very poor outcomes and should be considered for alternative therapeutic strategies.

Optimizing Somatostatin Receptor Imaging in Patients With Neuroendocrine Tumors: The Impact of 99mTc-HYNICTOC SPECT/SPECT/CT Versus 68Ga-DOTATATE PET/CT Upon Clinical Management.

AIM: The presence of somatostatin receptors in neuroendocrine tumors allows visualization with radiolabeled somatostatin analogs in vivo. The aim of this prospective study was to compare somatostatin receptor imaging using Tc-HYNICTOC with Ga-DOTATATE (DOTA-DPhe1,Tyr3-octreotate) with respect to sensitivity, specificity, and impact upon clinical decision making. METHODS: Sixty-eight patients (30 men, 38 women; aged 56.4 ± 13.5 years) with disseminated, histologically proven neuroendocrine tumor were enrolled. All patients with previous Tc-HYNICTOC (Tektrotyd; POLATOM, Otwock, Poland) underwent Ga-DOTATATE PET/CT. Both examinations were compared on a per-patient and per-lesion basis. RESULTS: The sensitivity, specificity, positive and negative predictive values, and accuracy of Ga-DOTATATE and Tc-HYNICTOC were 100% versus 82%, 85% versus 69%, 97% versus 92%, 100% versus 47%, and 97% versus 79%, respectively.Concordant results were observed in 58 patients (49/68 positive on both Ga-DOTATATE and Tc-HYNICTOC and 9/68 negative in both examinations). Ten of 68 patients had Ga-DOTATATE-positive, Tc-HYNICTOC-negative studies. Two hundred eighteen lesions were detected using Tc-HYNICTOC, compared with 546 lesions using Ga-DOTATATE (P < 0.0001). Ga-DOTATATE detected a higher number of lesions in bone and lymph nodes, liver, intestine, and pancreas and had a higher sensitivity for subcentimeter abnormalities than Tc-HYNICTOC. Ga-DOTATATE led to management change in 23 (34%) of 68 patients. CONCLUSIONS: Ga-DOTATATE has a higher sensitivity than Tc-HYNICTOC for the detection of neuroendocrine tumors. Ga-DOTATATE proved superior to Tc-HYNICTOC in detecting subcentimeter skeletal, lymph node, and liver metastases. Ga-DOTATATE PET/CT changed clinical decision making in one third of patients.

Re-assessing gallium-67 as a therapeutic radionuclide.

INTRODUCTION: Despite its desirable half-life and low energy Auger electrons that travel further than for other radionuclides, 67Ga has been neglected as a therapeutic radionuclide. Here, 67Ga is compared with Auger electron emitter 111In as a potential therapeutic radionuclide. METHODS: Plasmid pBR322 studies allowed direct comparison between 67Ga and 111In (1MBq) in causing DNA damage, including the effect of chelators (EDTA and DTPA) and the effects of a free radical scavenger (DMSO). The cytotoxicity of internalized (by means of delivery in the form of oxine complexes) and non-internalized 67Ga and 111In was measured in DU145 prostate cancer cells after a one-hour incubation using cell viability (trypan blue) and clonogenic studies. MDA-MB-231 and HCC1954 cells were also used. RESULTS: Plasmid DNA damage was caused by 67Ga and was comparable to that caused by 111In; it was reduced in the presence of EDTA, DTPA and DMSO. The A50 values (internalized activity of oxine complexes per cell required to kill 50% of cells) as determined by trypan blue staining was 1.0Bq/cell for both 67Ga and 111In; the A50 values determined by clonogenic assay were 0.7Bq/cell and 0.3Bq/cell for 111In and 67Ga respectively. At the concentrations required to achieve these uptake levels, non-internalized 67Ga and 111In caused no cellular toxicity. Qualitatively similar results were found for MDA-MB-231 and HCC1954 cells. CONCLUSION: 67Ga causes as much damage as 111In to plasmid DNA in solution and shows similar toxicity as 111In at equivalent internalized activity per cell. 67Ga therefore deserves further evaluation for radionuclide therapy. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: The data presented here is at the basic level of science. If future in vivo and clinical studies are successful, 67Ga could become a useful radionuclide with little healthy tissue toxicity in the arsenal of weapons for treating cancer.

A Phase 1, Open-Label Study of the Biodistribution, Pharmacokinetics, and Dosimetry of 223Ra-Dichloride in Patients with Hormone-Refractory Prostate Cancer and Skeletal Metastases.

UNLABELLED: The aim of this single-site, open-label clinical trial was to determine the biodistribution, pharmacokinetics, absorbed doses, and safety from 2 sequential weight-based administrations of (223)Ra-dichloride in patients with bone metastases due to castration-refractory prostate cancer. METHODS: Six patients received 2 intravenous injections of (223)Ra-dichloride, 6 wk apart, at 100 kBq/kg of whole-body weight. The pharmacokinetics and biodistribution as a function of time were determined, and dosimetry was performed for a range of organs including bone surfaces, red marrow, kidneys, gut, and whole body using scintigraphic imaging; external counting; and blood, fecal, and urine collection. Safety was assessed from adverse events. RESULTS: The injected activity cleared rapidly from blood, with 1.1% remaining at 24 h. The main route of excretion was via the gut, although no significant toxicity was reported. Most of the administered activity was taken up rapidly into bone (61% at 4 h). The range of absorbed doses delivered to the bone surfaces from α emissions was 2,331-13,118 mGy/MBq. The ranges of absorbed doses delivered to the red marrow were 177-994 and 1-5 mGy/MBq from activity on the bone surfaces and from activity in the blood, respectively. No activity-limiting toxicity was observed at these levels of administration. The absorbed doses from the second treatment were correlated significantly with the first for a combination of the whole body, bone surfaces, kidneys, and liver. CONCLUSION: A wide range of interpatient absorbed doses was delivered to normal organs. Intrapatient absorbed doses were significantly correlated between the 2 administrations for any given patient. The lack of gastrointestinal toxicity is likely due to the low absorbed doses delivered to the gut wall from the gut contents. The lack of adverse myelotoxicity implies that the absorbed dose delivered from the circulating activity may be a more relevant guide to the potential for marrow toxicity than that due to activity on the bone surfaces.

Role of SPECT/CT in differentiated thyroid cancer.

Radioiodine scintigraphy and therapy has played a major role in the treatment and follow-up of thyroid cancer patients for decades. Single-photon emission computed tomography/computed tomography in this setting is emerging as a useful tool in accurately localizing sites of pathological uptake and physiological mimics of disease, thus providing more accurate staging prognostic information for risk stratification, which in turn tailors management and follow-up regimes. This review presents the current evidence and potential indications of single-photon emission computed tomography/computed tomography in thyroid cancer.

Neuroendocrine tumor liver metastases: use of dynamic contrast-enhanced MR imaging to monitor and predict radiolabeled octreotide therapy response.

PURPOSE: To evaluate dynamic contrast-enhanced (DCE) magnetic resonance (MR) imaging for monitoring and assessing treatment response in patients with neuroendocrine liver metastases treated using yttrium 90 ((90)Y)-labeled octreotide ((90)Y-DOTATOC). MATERIALS AND METHODS: The study was approved by the local research and ethics committee and patient informed consent was obtained. Twenty patients with liver metastases from neuroendocrine tumors underwent T1-weighted DCE MR imaging of the liver before and at 2 months after intravenous (90)Y-DOTATOC treatment. Regions of interest were drawn around target lesions, as well as along liver outlines for each patient. A dual-input single-compartment model was used to compute parameters including fractional distribution volume and the arterial flow fraction. Pre- and posttreatment values were compared using Wilcoxon signed rank test. Treatment response was defined as showing a greater than 50% reduction in the nadir chromogranin A level within the 1st year after treatment. Pretreatment values of responders and nonresponders were compared using the Mann-Whitney test. A two-tailed P value of .008 or less, which accounts for multiple testing, was considered to indicate a significant difference. RESULTS: In responders, tumor and whole liver distribution volume significantly increased after treatment (median tumor distribution volume, 0.182 vs 0.244; median whole liver distribution volume, 0.175 vs 0.207; P = .008). The pretreatment whole liver distribution volume was significantly lower in responders (median, 0.175 vs 0.248; P = .003), while pretreatment tumor arterial flow fraction was significantly higher in responders (median, 1.000 vs 0.7 ± 1, P = .006). CONCLUSION: DCE MR imaging may be used to monitor the effects of peptide receptor radiolabeled targeted therapy in patients with neuroendocrine tumors liver metastases; a lower pretreatment distribution volume and high arterial flow fraction was associated with a better response to treatment.

Guidelines for imaging and staging of neuroblastic tumors: consensus report from the International Neuroblastoma Risk Group Project.

Neuroblastoma is an enigmatic disease entity; some tumors disappear spontaneously without any therapy, while others progress with a fatal outcome despite the implementation of maximal modern therapy. However, strong prognostic factors can accurately predict whether children have "good" or "bad" disease at diagnosis, and the clinical stage is currently the most significant and clinically relevant prognostic factor. Therefore, for an individual patient, proper staging is of paramount importance for risk assessment and selection of optimal treatment. In 2009, the International Neuroblastoma Risk Group (INRG) Project proposed a new staging system designed for tumor staging before any treatment, including surgery. Compared with the focus of the International Neuroblastoma Staging System, which is currently the most used, the focus has now shifted from surgicopathologic findings to imaging findings. The new INRG Staging System includes two stages of localized disease, which are dependent on whether image-defined risk factors (IDRFs) are or are not present. IDRFs are features detected with imaging at the time of diagnosis. The present consensus report was written by the INRG Imaging Committee to optimize imaging and staging and reduce interobserver variability. The rationales for using imaging methods (ultrasonography, magnetic resonance imaging, computed tomography, and scintigraphy), as well as technical guidelines, are described. Definitions of the terms recommended for assessing IDRFs are provided with examples. It is anticipated that the use of standardized nomenclature will contribute substantially to more uniform staging and thereby facilitate comparisons of clinical trials conducted in different parts of the world.

The diagnostic utility of the flare phenomenon on bone scintigraphy in staging prostate cancer.

PURPOSE: Bone scintigraphy (BS) lacks sensitivity for detecting very early skeletal metastases (SM) in prostate cancer (PC) and is often limited by poor specificity. Also scintigraphic flare of SM can occur following effective treatment and mislead an early response assessment. We hypothesised that a flare reaction might amplify the signal from subclinical SM, increasing the sensitivity of BS and that the phenomenon may be specific for metastases. METHODS: We conducted a prospective study to determine the frequency of the flare phenomenon in patients with metastatic PC starting hormone therapy and to explore its utility in patients with negative staging scans but considered at high risk of SM and in those with equivocal baseline BS abnormalities. Ninety-nine patients commencing first-line hormone therapy had repeat BS at 6 weeks to score a flare reaction. RESULTS: Of 22 patients with unequivocal SM on the baseline scan, a flare occurred in 9 (41%). Of 36 high-risk localised prostate cancer patients with normal BS pre-treatment, the scan became positive for metastases at 6 weeks in 4 (11%). Of 41 patients with pre-treatment scintigraphic abnormalities of uncertain aetiology, a flare occurred in 8 cases (20%). All eight were confirmed to have SM by follow-up and imaging. Of the 33 remaining patients without a flare, 2 developed SM at 14 months and the remainder did not develop SM in a median follow-up period of 36 months. CONCLUSION: The flare phenomenon following initial hormone therapy can be used to improve both sensitivity and specificity of BS in PC.

Phase 1/2 study of fractionated (131)I-rituximab in low-grade B-cell lymphoma: the effect of prior rituximab dosing and tumor burden on subsequent radioimmunotherapy.

The effect of induction therapy with multiple doses of rituximab on the subsequent efficacy and toxicity of anti-CD20 radioimmunotherapy is unknown. We evaluated a novel protocol using 4 weekly infusions of 375 mg/m(2) rituximab followed by 2 fractions of (131)I-rituximab, preceded by a 100-mg/m(2) predose of rituximab, in relapsed indolent B-cell lymphoma. Induction therapy with rituximab significantly increased the effective half-life of (131)I-rituximab (P = .003) and high serum levels of rituximab after induction therapy correlated with increased effective half-life of the radioimmunoconjugate (P = .009). Patients with large tumor burdens experienced significant increases in the effective half-life of (131)I-rituximab between delivery of the first and second fractions (P = .007). Induction therapy with multiple doses of rituximab did not appear to compromise the clinical efficacy or increase toxicity of subsequent (131)I-rituximab radioimmunotherapy. The overall response rate was 94%, with complete response rate 50%. The median time to progression was 20 months, significantly longer than for the last qualifying chemotherapy (P = .001). Fractionation of (131)I-rituximab allowed cumulative whole-body doses of more than 120 cGy, approximately 60% greater than those previously achieved with a single administration of a murine radioimmunconjugate, to be delivered without significant hematologic toxicity.

Development of 131I-tositumomab.

The median survival for patients with advanced indolent non-Hodgkin's lymphoma (NHL) has remained at 7 to 8 years since the 1960s. Targeted treatment using radioimmunotherapy (RIT), radiolabeled monoclonal antibodies directed against tumor-specific antigens, is an attractive option for this patient population, combining the advantages of an active biologic therapy with low dose-rate irradiation of an inherently radiosensitive tumor. Two anti-CD20 RIT agents have now been approved for the treatment of refractory NHL: 90Y-ibritumomab tiuxetan (Zevalin; Biogen Idec Inc, San Diego, CA, and Schering AG, Berlin, Germany) is approved in both the United States and Europe, and 131I-tositumomab (Bexxar; Corixa Corp, Seattle, WA) is approved only in the United States. This article discusses the development of 131I-tositumomab. Because 131I-labeled antibody clearance varies significantly among patients, prescription of 131I-tositumomab activity must be based on a calculated total-body dose derived from quantitative whole-body imaging. The maximum tolerated total-body dose has been established at 75 cGy in patients with adequate bone marrow reserves and less than 25% bone marrow involvement by lymphoma (65 cGy in patients with mild thrombocytopenia; 45 cGy in patients who have received stem cell transplantation). In a phase III trial, overall response rate (ORR) and complete response (CR) rate were significantly higher following 131I-tositumomab than following the patient's last qualifying chemotherapy (ORR, 65% v 28%; P <.001; CR, 20% v 3%; P <.001). 131I-tositumomab has also been shown to be effective in patients who are refractory to rituximab (ORR, 70%; CR, 32%) and as first-line therapy in patients with NHL (ORR, 97%; CR, 63%). The major side effects of 131I-tositumomab are hematologic. In the phase III study, 20% of patients experienced grade 4 neutropenia and 22% experienced grade 4 thrombocytopenia. Myelodysplastic syndromes or secondary acute myeloid leukemia have been reported in 8.4% of patients with chemotherapy-refractory disease treated with 131I-tositumomab, but have not been observed to date in patients receiving 131I-tositumomab as first-line therapy. Future progress in NHL management is likely to include RIT as part of a multi-modality approach; trials are planned or currently underway to investigate the combination of RIT with chemotherapy regimens.