Statistical assessment of treatment response in a cancer patient based on pre-therapy and post-therapy FDG-PET scans.

This work arises from consideration of sarcoma patients in which fluorodeoxyglucose positron emission tomography (FDG-PET) imaging pre-therapy and post-chemotherapy is used to assess treatment response. Our focus is on methods for evaluation of the statistical uncertainty in the measured response for an individual patient. The gamma distribution is often used to describe data with constant coefficient of variation, but it can be adapted to describe the pseudo-Poisson character of PET measurements. We propose co-registering the pre-therapy and post- therapy images and modeling the approximately paired voxel-level data using the gamma statistics. Expressions for the estimation of the treatment effect and its variability are provided. Simulation studies explore the performance in the context of testing for a treatment effect. The impact of misregistration errors and how test power is affected by estimation of variability using simplified sampling assumptions, as might be produced by direct bootstrapping, is also clarified. The results illustrate a marked benefit in using a properly constructed paired approach. Remarkably, the power of the paired analysis is maintained even if the pre-image and post- image data are poorly registered. A theoretical explanation for this is indicated. The methodology is further illustrated in the context of a series of fluorodeoxyglucose-PET sarcoma patient studies. These data demonstrate the additional prognostic value of the proposed treatment effect test statistic. Copyright © 2016 John Wiley & Sons, Ltd.

A statistical modeling approach to the analysis of spatial patterns of FDG-PET uptake in human sarcoma.

Clinical experience with positron emission tomography (PET) scanning of sarcoma, using fluorodeoxyglucose (FDG), has established spatial heterogeneity in the standardized uptake values within the tumor mass as a key prognostic indicator of patient survival. But it may be that a more detailed quantitation of the tumor FDG uptake pattern could provide additional insights into risk. The present work develops a statistical model for this purpose. The approach is based on a tubular representation of the tumor mass with a simplified radial analysis of uptake, transverse to the tubular axis. The technique provides novel ways of characterizing the overall profile of the tumor, including the introduction of an approach for the measurement of its phase of development. The phase measure can distinguish between early phase tumors, in which the uptake is highest at the core, and later stage masses, in which there can often be central voids in FDG uptake. Biologically, these voids arise from necrosis and fluid, fat or cartilage accumulations. The tumor profiling technique is implemented using open-source software tools and illustrations are provided with clinically representative scans. A series of FDG-PET studies from 185 patients is used to formally evaluate the prognostic benefit. Significant improvements in the prediction of patient survival and progression are obtained from the tumor profiling analysis. After adjustment for other factors including heterogeneity, a typical one standard deviation increase in phase (as determined by the analysis) is associated with close to 20% more risk of progression or death. The work confirms that more detailed quantitative assessments of the spatial pattern of PET imaging data of tumor masses, beyond the maximum FDG uptake (SUV(max)) and previously considered measures of heterogeneity, provide improved prognostic information for potential input to treatment decisions for future patients.

Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group Bone Tumor Committee.

The Children's Oncology Group (COG) is a multi-institutional cooperative group dedicated to childhood cancer research that has helped to increase the survival of children with cancer through clinical trials. These clinical trials include a standardized regimen of imaging examinations performed prior to, during, and following therapy. This article presents imaging guidelines developed by a multidisciplinary group from the COG Bone Tumor Committee. These guidelines provide both required and recommended studies. Recommended examinations may become required in the future. These guidelines should be considered a work in progress that will evolve with advances in imaging and childhood cancer research.

[(18)F]FMISO and [(18)F]FDG PET imaging in soft tissue sarcomas: correlation of hypoxia, metabolism and VEGF expression.

Hypoxia imparts resistance to radiotherapy and chemotherapy and also promotes a variety of changes in tumor biology through inducible promoters. The purpose of this study was to evaluate the use of positron emission tomography (PET) imaging with fluorine-18 fluoromisonidazole (FMISO) in soft tissue sarcomas (STS) as a measure of hypoxia and to compare the results with those obtained using [(18)F]fluorodeoxyglucose (FDG) and other known biologic correlates. FDG evaluates energy metabolism in tumors while FMISO uptake is proportional to tissue hypoxia. FMISO uptake was compared with FDG uptake. Vascular endothelial growth factor (VEGF) expression was also compared with FMISO uptake. Nineteen patients with STS underwent PET scanning with quantitative determination of FMISO and FDG uptake prior to therapy (neo-adjuvant chemotherapy or surgery alone). Ten patients receiving neo-adjuvant chemotherapy were also imaged after chemotherapy but prior to surgical resection. Standardized uptake value (SUV) was used to describe FDG uptake; regional tissue to blood ratio (>or=1.2 was considered significant) was used for FMISO uptake. Significant hypoxia was found in 76% of tumors imaged prior to therapy. No correlation was identified between pretherapy hypoxic volume (HV) and tumor grade ( r=0.15) or tumor volume ( r=0.03). The correlation of HV with VEGF expression was 0.39. Individual tumors showed marked heterogeneity in regional VEGF expression. The mean pixel-by-pixel correlation between FMISO and FDG uptake was 0.49 (range 0.09-0.79) pretreatment and 0.32 (range -0.46-0.72) after treatment. Most tumors showed evidence of reduced uptake of both FMISO and FDG following chemotherapy. FMISO PET demonstrates areas of significant and heterogeneous hypoxia in soft tissue sarcomas. The significant discrepancy between FDG and FMISO uptake seen in this study indicates that regional hypoxia and glucose metabolism do not always correlate. Similarly, we did not find any relationship between the hypoxic volume and the tumor volume or VEGF expression. Identification of hypoxia and development of a more complete biologic profile of STS will serve to guide more rational, individualized cancer treatment approaches.

18fluorodeoxyglucose positron emission tomography to detect mediastinal or internal mammary metastases in breast cancer.

PURPOSE: To determine the prevalence of suspected disease in the mediastinum and internal mammary (IM) node chain by 18fluorodeoxyglucose (FDG) positron emission tomography (PET), compared with conventional staging by computed tomography (CT) in patients with recurrent or metastatic breast cancer. PATIENTS AND METHODS: We retrospectively evaluated intrathoracic lymph nodes using FDG PET and CT data in 73 consecutive patients with recurrent or metastatic breast cancer who had both CT and FDG PET within 30 days of each other. In reviews of CT scans, mediastinal nodes measuring 1 cm or greater in the short axis were considered positive. PET was considered positive when there were one or more mediastinal foci of FDG uptake greater than the mediastinal blood pool. RESULTS: Overall, 40% of patients had abnormal mediastinal or IM FDG uptake consistent with metastases, compared with 23% of patients who had suspiciously enlarged mediastinal or IM nodes by CT. Both FDG PET and CT were positive in 22%. In the subset of 33 patients with assessable follow-up by CT or biopsy, the sensitivity, specificity, and accuracy for nodal disease was 85%, 90%, and 88%, respectively, by FDG PET; 54%, 85%, and 73%, respectively, by prospective interpretation of CT; and 50%, 83%, and 70%, respectively, by blinded observer interpretation of CT. Among patients suspected of having only locoregional disease recurrence (n = 33), 10 had unsuspected mediastinal or IM disease by FDG PET. CONCLUSION: FDG PET may uncover disease in these nodal regions not recognized by conventional staging methods. Future prospective studies using histopathology for confirmation are needed to validate the preliminary findings of this retrospective study.

Imaging cellular proliferation as a measure of response to therapy.

Cell proliferation imaging is based on extensive laboratory investigations of labeled thymidine being selectively incorporated into DNA. [11C]-Thymidine labeled in the ring-2 or the methyl position is the natural extension of earlier work using tritiated thymidine. Proliferation imaging using [11C]-thymidine requires correction for labeled metabolites; however, quantitative approaches can provide reliable estimates of cellular proliferation by measuring thymidine flux from the blood into DNA in tumors. 18F-labeled thymidine analogs that are resistant to catabolism in vivo, [18F]-FLT and [18F]-FMAU, may simplify quantitative analysis and may be more suitable for clinical studies but will require careful validation to determine how their uptake is quantitatively related to cell growth. Clinical studies using [11C]-thymidine have demonstrated the power of cellular proliferation imaging to characterize tumors and monitor response early in the course of therapy. Patient imaging using the PET thymidine analogs is at an earlier stage but appears promising as a clinically feasible approach to cellular proliferation imaging.

Internal mammary lymph node drainage patterns in patients with breast cancer documented by breast lymphoscintigraphy.

BACKGROUND: Metastases to internal mammary lymph nodes (IMN) may occur in patients with breast cancer and may alter treatment recommendations. The purpose of this study was to identify the frequency of IMN drainage in patients undergoing breast lymphoscintigraphy and sentinel lymph node dissection (SLND). METHODS: The combined technique of peritumoral injection of radiocolloid and Lymphazurin blue for SLND was performed on 220 patients. All patients underwent preoperative lymphoscintigraphy before SLND. Lesion location by quadrant included: 110 upper outer (UOQ), 49 lower outer (LOQ), 30 upper inner (UIQ), 24 lower inner (LIQ), and 7 central. RESULTS: Drainage to any nodal basin was observed in 184 of 220 patients (84%). IMN drainage was documented in 37 of 220 (17%) of patients. IMN drainage without evidence of axillary drainage occurred in 2 of 220 patients(1%). Drainage to the IMN based on quadrant location of the lesion was as follows: UOQ, 10%; LOQ, 27%; UIQ, 17%; LIQ, 25%; and central, 29%. CONCLUSIONS: Internal mammary lymph node drainage shown by breast lymphoscintigraphy is common. Tumors in all quadrants may drain to IMNs, although drainage is significantly more common from quadrants other than the UOQ. Further studies are needed to determine whether lymphoscintigraphy drainage patterns identify patients at the highest risk for IMN metastases who may benefit from radiotherapy.

A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas.

Relapsed B-cell lymphomas are incurable with conventional chemotherapy and radiation therapy, although a fraction of patients can be cured with high-dose chemoradiotherapy and autologous stem-cell transplantation (ASCT). We conducted a phase I/II trial to estimate the maximum tolerated dose (MTD) of iodine 131 ((131)I)-tositumomab (anti-CD20 antibody) that could be combined with etoposide and cyclophosphamide followed by ASCT in patients with relapsed B-cell lymphomas. Fifty-two patients received a trace-labeled infusion of 1.7 mg/kg (131)I-tositumomab (185-370 MBq) followed by serial quantitative gamma-camera imaging and estimation of absorbed doses of radiation to tumor sites and normal organs. Ten days later, patients received a therapeutic infusion of 1.7 mg/kg tositumomab labeled with an amount of (131)I calculated to deliver the target dose of radiation (20-27 Gy) to critical normal organs (liver, kidneys, and lungs). Patients were maintained in radiation isolation until their total-body radioactivity was less than 0.07 mSv/h at 1 m. They were then given etoposide and cyclophosphamide followed by ASCT. The MTD of (131)I-tositumomab that could be safely combined with 60 mg/kg etoposide and 100 mg/kg cyclophosphamide delivered 25 Gy to critical normal organs. The estimated overall survival (OS) and progression-free survival (PFS) of all treated patients at 2 years was 83% and 68%, respectively. These findings compare favorably with those in a nonrandomized control group of patients who underwent transplantation, external-beam total-body irradiation, and etoposide and cyclophosphamide therapy during the same period (OS of 53% and PFS of 36% at 2 years), even after adjustment for confounding variables in a multivariable analysis.

(F-18) fluorodeoxyglucose positron emission tomography as a predictor of pathologic grade and other prognostic variables in bone and soft tissue sarcoma.

Positron emission tomography (PET) can be used to measure tumor metabolism in sarcomas by measuring the standard uptake value (SUV) of (F-18) fluorodeoxyglucose (FDG). FDG-PET SUV has been shown to correlate with histological grade. We compared FDG-PET SUV in 89 bone and soft tissue sarcomas with histopathological features, including tumor grade, as well as with markers of cell proliferation and cell cycle regulatory gene expression that may be prognostically or therapeutically important. All patients had undergone PET before biopsy. Features evaluated included grade (National Cancer Institute for soft tissue or Mayo Clinic for bone), cellularity, and the number of mitoses per 10 400x fields. Deparaffinized, formalin-fixed sections were immunostained with antibodies to Ki-67 (MIB-1), p53 (DO7), p21WAF1 (EA10), and mdm-2 (1B10). For Ki-67, results were estimated as a percentage of positive cells. For p53 and mdm-2, only cases with >20% positive cells were considered to be overexpressing these proteins. For p21WAF1, only cases with <10% positive cells were considered to have lost normal p21WAF1 expression. Tumor S-phase percentage and ploidy were determined by flow cytometry. FDG-PET SUV was associated with histopathological grade, cellularity, mitotic activity, MIB labeling index, and p53 overexpression. No association was seen with p21WAF1, mdm-2, S-phase fraction, or ploidy. Tumor metabolism data acquired by FDG-PET may help ensure accurate grading and prognostication in sarcoma by guiding biopsy toward the most biologically significant regions of large masses. Further follow-up will be necessary to determine whether FDG-PET provides independent prognostic information.

Increased false negative sentinel node biopsy rates after preoperative chemotherapy for invasive breast carcinoma.

BACKGROUND: Sentinel lymph node dissection (SLND) has been a promising new technique in breast carcinoma staging, but could be unreliable in certain patient subsets. The current study assessed whether age, preoperative chemotherapy, tumor size, and/or previous excisional biopsy influenced the identification of sentinel nodes (SLNs) or the reliability of a node-negative SLND in predicting a node negative axilla. METHODS: Eighty-two patients who had clinically negative axillae underwent SLND followed by Level I/II axillary lymph node dissection (ALND). SLNDs were performed using both technetium-99m (Tc-99m) labeled colloid and isosulfan blue dye. SLNs were analyzed by hematoxlyin and eosin and immunocytochemical techniques. RESULTS: SLNs were successfully identified in 80% of patients. Mapping success was decreased among postmenopausal women but was not influenced by preoperative chemotherapy, large tumor size, or previous excisional biopsy. Of the 31 successfully mapped, node positive patients, 5 had false negative (FN) SLNDs (overall FN rate = 16%). Of the 9 successfully mapped patients who had received preoperative chemotherapy and had positive axillary nodes, 3 had FN SLND (FN rate = 33%). The presence of clinically positive lymph nodes before chemotherapy did not predict which patients would have a subsequent FN SLND. T3 tumor size, but not previous excision, was associated significantly with increased FN rate, although the FN rate for previous excision was 11%. No FN SLND occurred with T1/T2 tumors that were not excised previously and had not received preoperative chemotherapy. CONCLUSIONS: Preoperative chemotherapy was associated with an unacceptably high FN rate for SLND. While larger tumor size also was associated with FN SLND, this effect might have been due to preoperative chemotherapy use in these patients. Small sample size precluded determining whether excisional biopsy before mapping increased FN SLND rates independently.

Sentinel lymph node mapping for breast cancer: analysis in a diverse patient group.

PURPOSE: To evaluate sentinel lymph node mapping in patients with breast cancer. MATERIALS AND METHODS: Sixty-two patients with breast cancer scheduled to undergo axillary nodal dissection underwent scintigraphic localization of sentinel lymph nodes with filtered technetium 99m sulfur colloid. At surgery, isosulfan blue was injected. Sentinel nodes were identifiable by blue color and by radioactivity with hand-held gamma probe. Results were analyzed statistically. RESULTS: A sentinel lymph node was identified in 49 patients (79%). Lymph nodes were positive for metastatic disease in 26 patients (42%). The mapping success rate was 78% (n = 21) in the 27 patients with no prior surgery, 78% (n = 18) in the 23 patients with prior surgery, and 86% (n = 12) in the 14 patients with prior chemotherapy. Axillary nodes were positive in 11 (41%) of the 27 patients with no prior intervention, six (26%) of the 23 patients with prior surgery, and 10 (71%) of the 14 patients with prior chemotherapy. There were no false-negative findings in patients without prior intervention. Four patients with positive nodes had false-negative sentinel nodes. CONCLUSION: Sentinel lymph node mapping and biopsy without axillary dissection is appropriate in patients with breast cancer who have not undergone prior intervention. Further study is necessary to ascertain the accuracy of the procedure for patients who have undergone presurgical chemotherapy or previous excisional biopsy.

Nuclear medicine in cancer diagnosis.

Nuclear medicine imaging has contributed significantly to diagnosis, treatment planning, and the evaluation of response to treatment in patients with cancer since the development of modern techniques in the 1970s. Diagnostic applications such as the bone scan continue to be the most common use in oncology because of their high sensitivity but the contribution of nuclear medicine to oncology can perhaps be best understood in the context of patient management. Staging of newly presenting cancer patients and restaging for treatment planning are reviewed here. For treatment response and disease recurrence nuclear medicine provides information non-invasively. The studies can be repeated with few side-effects and with low radiation absorbed doses. Results can be directly correlated with clinical laboratory data. The goals of biologically characterising an individual patient's tumour and predicting his or her response to treatment are within reach.

Phase I study of (131)I-anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic syndrome.

Delivery of targeted hematopoietic irradiation using radiolabeled monoclonal antibody may improve the outcome of marrow transplantation for advanced acute leukemia by decreasing relapse without increasing toxicity. We conducted a phase I study that examined the biodistribution of (131)I-labeled anti-CD45 antibody and determined the toxicity of escalating doses of targeted radiation combined with 120 mg/kg cyclophosphamide (CY) and 12 Gy total body irradiation (TBI) followed by HLA-matched related allogeneic or autologous transplant. Forty-four patients with advanced acute leukemia or myelodysplasia received a biodistribution dose of 0.5 mg/kg (131)I-BC8 (murine anti-CD45) antibody. The mean +/- SEM estimated radiation absorbed dose (centigray per millicurie of (131)I) delivered to bone marrow and spleen was 6.5 +/- 0.5 and 13.5 +/- 1.3, respectively, with liver, lung, kidney, and total body receiving lower amounts of 2.8 +/- 0.2, 1.8 +/- 0.1, 0.6 +/- 0.04, and 0.4 +/- 0.02, respectively. Thirty-seven patients (84%) had favorable biodistribution of antibody, with a higher estimated radiation absorbed dose to marrow and spleen than to normal organs. Thirty-four patients received a therapeutic dose of (131)I-antibody labeled with 76 to 612 mCi (131)I to deliver estimated radiation absorbed doses to liver (normal organ receiving the highest dose) of 3.5 Gy (level 1) to 12.25 Gy (level 6) in addition to CY and TBI. The maximum tolerated dose was level 5 (delivering 10.5 Gy to liver), with grade III/IV mucositis in 2 of 2 patients treated at level 6. Of 25 treated patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS), 7 survive disease-free 15 to 89 months (median, 65 months) posttransplant. Of 9 treated patients with acute lymphoblastic leukemia (ALL), 3 survive disease-free 19, 54, and 66 months posttransplant. We conclude that (131)I-anti-CD45 antibody can safely deliver substantial supplemental doses of radiation to bone marrow (approximately 24 Gy) and spleen (approximately 50 Gy) when combined with conventional CY/TBI.

Technical aspects of sentinel node lymphoscintigraphy for breast cancer.

OBJECTIVE: A significant morbidity risk is associated with axillary nodal dissections for breast cancer. Many treatment decisions are based on axillary nodal status. Lymphatic mapping and sentinel node biopsy have been investigated to determine if the histology of the sentinel node reflects the remaining lymph node basin. We describe the technical aspects of sentinel node lymphoscintigraphy for breast cancer. METHODS: Ninety-three patients had lymphoscintigraphy for breast cancer. Patients with palpable lesions had 4 concentric injections around the site and lesions requiring localization had injections made through tubing connected to the localizing wire introducer needle. Immediate static images were acquired and the sentinel node was marked for surgery. Marks were reverified using a handheld gamma probe. RESULTS: Lymph nodes were visualized by lymphoscintigraphy in 87% of cases. Time to visualization of lymph nodes ranged from 1-120 min with a mean of 28 min. An average of 1.5 nodes were visualized. The overall success rate for identifying the sentinel node at time of surgery was 85%. CONCLUSION: We conclude that lymphoscintigraphy for breast cancer is a detailed procedure that requires coordination with radiology and surgery teams to ensure proper identification of sentinel lymph nodes.

Kinetic analysis of 2-[11C]thymidine PET imaging studies: validation studies.

UNLABELLED: 2-[11C]thymidine has been tested as a PET tracer of cellular proliferation. We have previously described a model of thymidine and labeled metabolite kinetics for use in quantifying the flux of thymidine into DNA as a measure of tumor proliferation. We describe here the results of studies to validate some of the model's assumptions and to test the model's ability to predict the time course of tracer incorporation into DNA in tumors. METHODS: Three sets of studies were conducted: (a) The uptake of tracers in proliferative tissues of normal mice was measured early after injection to assess the relative delivery of thymidine and metabolites of thymidine catabolism (thymine and CO2) and calculate relative blood-tissue transfer rates (relative K1s). (b) By using sequential injections of [11C]thymidine and [11C]thymine in normal human volunteers, the kinetics of the first labeled metabolite were measured to determine whether it was trapped in proliferating tissue such as the bone marrow. (c) In a multitumor rat model, 2-[14C]thymidine injection, tumor sampling and quantitative DNA extraction were performed to measure the time course of label uptake into DNA for comparison with model predictions. RESULTS: Studies in mice showed consistent relative delivery of thymidine and metabolites in somatic tissue but, as expected, showed reduced delivery of thymidine and thymine in the normal brain compared to CO2. Thymine studies in volunteers showed only minimal trapping of label in bone marrow in comparison to thymidine. This quantity of trapping could be explained by a small amount of fixation of labeled CO2 in tissue, a process that is included as part of the model. Uptake experiments in rats showed early incorporation of label into DNA, and the model was able to fit the time course of uptake. CONCLUSION: These initial studies support the assumptions of the compartmental model and demonstrate its ability to quantify thymidine flux into DNA by using 2-[11C]thymidine and PET. Results suggest that further work will be necessary to investigate the effects of tumor heterogeneity and to compare PET measures of tumor proliferation to in vitro measures of proliferation and to clinical tumor behavior in patients undergoing therapy.

2-[C-11]thymidine imaging of malignant brain tumors.

Malignant brain tumors pose diagnostic and therapeutic problems. Despite the advent of new brain imaging modalities, including magnetic resonance imaging (MRI) and [F-18]fluorodeoxyglucose (FDG) positron emission tomography (PET), determination of tumor viability and response to treatment is often difficult. Blood-brain barrier disruption can be caused by tumor or nonspecific reactions to treatment, making MRI interpretation ambiguous. The high metabolic background of the normal brain and its regional variability makes it difficult to identify small or less active tumors by FDG imaging of cellular energetics. We have investigated 2-[C-11]thymidine (dThd) and PET to image the rate of brain tumor cellular proliferation. A series of 13 patients underwent closely spaced dThd PET, FDG PET, and MRI procedures, and the image results were compared by standardized visual analysis. The resulting dThd scans were qualitatively different from the other two scans in approximately 50% of the cases, which suggests that dThd provided information distinct from FDG PET and MRI. In two cases, recurrent tumor was more apparent on the dThd study than on FDG; in two other patients, tumor dThd uptake was less than FDG uptake, and these patients had slower tumor progression than the three patients with both high dThd and FDG uptake. To better characterize tumor proliferation, kinetic modeling was applied to dynamic dThd PET uptake data and metabolite-analyzed blood data in a subset of patients. Kinetic analysis was able to remove the confounding influence of [C-11]CO2, the principal labeled metabolite of 2-[C-11]dThd, and to estimate the flux of dThd incorporation into DNA. Sequential, same-day [C-11]CO2 and [C-11]dThd imaging demonstrated the ability of kinetic analysis to model both dThd and CO2 simultaneously. Images of dThd flux obtained using the model along with the mixture analysis method for pixel-by-pixel parametric imaging significantly enhanced the contrast of tumor compared with normal brain. Comparison of model estimates of dThd transport versus dThd flux was able to discern increased dThd uptake simply on the basis of blood-brain barrier disruption retention on the basis of increased cellular proliferation. This preliminary study demonstrates the potential for imaging brain tumor cellular proliferation to provide unique information for guiding patient treatment.

Follow-up of relapsed B-cell lymphoma patients treated with iodine-131-labeled anti-CD20 antibody and autologous stem-cell rescue.

PURPOSE: Radioimmunotherapy (RIT) is a promising treatment approach for B-cell lymphomas. This is our first opportunity to report long-term follow-up data and late toxicities in 29 patients treated with myeloablative doses of iodine-131-anti-CD20 antibody (anti-B1) and autologous stem-cell rescue. PATIENTS AND METHODS: Trace-labeled biodistribution studies first determined the ability to deliver higher absorbed radiation doses to tumor sites than to lung, liver, or kidney at varying amounts of anti-B1 protein (0.35, 1.7, or 7 mg/kg). Twenty-nine patients received therapeutic infusions of single-agent (131)I-anti-B1, given at the protein dose found optimal in the biodistribution study, labeled with amounts of (131)I (280 to 785 mCi [10.4 to 29.0 GBq]) calculated to deliver specific absorbed radiation doses to the normal organs, followed by autologous stem-cell support. RESULTS: Major responses occurred in 25 patients (86%), with 23 complete responses (CRs; 79%). The nonhematopoietic dose-limiting toxicity was reversible cardiopulmonary insufficiency, which occurred in two patients at RIT doses that delivered > or = 27 Gy to the lungs. With a median follow-up time of 42 months, the estimated overall and progression-free survival rates are 68% and 42%, respectively. Currently, 14 of 29 patients remain in unmaintained remissions that range from 27+ to 87+ months after RIT. Late toxicities have been uncommon except for elevated thyroid-stimulating hormone (TSH) levels found in approximately 60% of the subjects. Two patients developed second malignancies, but none have developed myelodysplasia (MDS). CONCLUSION: Myeloablative (131)I-anti-B1 RIT is relatively well tolerated when given with autologous stem-cell support and often results in prolonged remission durations with few late toxicities.