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Journal of Clinical Oncology : Official... Mar 2018Purpose SWOG S0016 was a phase III randomized study that compared the safety and efficacy of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and... (Randomized Controlled Trial)
Randomized Controlled Trial
Continued Excellent Outcomes in Previously Untreated Patients With Follicular Lymphoma After Treatment With CHOP Plus Rituximab or CHOP Plus I-Tositumomab: Long-Term Follow-Up of Phase III Randomized Study SWOG-S0016.
Purpose SWOG S0016 was a phase III randomized study that compared the safety and efficacy of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) with CHOP-RIT (CHOP followed by consolidation with iodine-133-tositumomab radioimmunotherapy) for previously untreated patients with follicular lymphoma. Understanding the long-term outcome of patients provides a benchmark for novel treatment regimens for FL. Patients and Methods Between 2001 and 2008, 531 previously untreated patients with FL were randomly assigned to receive either six cycles of R-CHOP or six cycles of CHOP-RIT. Patients with advanced-stage disease (bulky stage II, III, or IV) of any pathologic grade (1, 2, or 3) were eligible. Results After a median follow-up of 10.3 years, 10-year estimates of progression-free and overall survival were 49% and 78% among all patients, respectively. Patients in the CHOP-RIT arm had significantly better 10-year progression-free survival compared with patients in the R-CHOP arm (56% v 42%; P = .01), but 10-year overall survival was not different between the two arms (75% v 81%; P = .13). There was no significant difference between the CHOP-RIT and R-CHOP arms in regard to incidence of second malignancies (15.1% v 16.1%; P = .81) or myelodysplastic syndrome or acute myeloid leukemia (4.9% v 1.8%; P = .058). The estimated 10-year cumulative incidences of death resulting from second malignancies were not different (7.1% v 3.2%; P = .16), but cumulative incidence of death resulting from myelodysplastic syndrome or acute myeloid leukemia was higher in the CHOP-RIT arm compared with the R-CHOP arm (4% v 0.9%; P = .02). Conclusion Given these outstanding outcomes, immunochemotherapy should remain the standard induction approach for patients with high-risk FL until long-term follow-up of alternative approaches demonstrates superiority.
Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cause of Death; Cyclophosphamide; Doxorubicin; Female; Follow-Up Studies; Humans; Lymphoma, Follicular; Male; Middle Aged; Neoplasms, Second Primary; Prednisone; Prognosis; Radioimmunotherapy; Rituximab; Vincristine
PubMed: 29356608
DOI: 10.1200/JCO.2017.74.5083 -
Journal of Nuclear Medicine : Official... Dec 2010This study aimed at identifying clinical factors for predicting hematologic toxicity after radioimmunotherapy with (90)Y-ibritumomab tiuxetan or (131)I-tositumomab in...
UNLABELLED
This study aimed at identifying clinical factors for predicting hematologic toxicity after radioimmunotherapy with (90)Y-ibritumomab tiuxetan or (131)I-tositumomab in clinical practice.
METHODS
Hematologic data were available from 14 non-Hodgkin lymphoma patients treated with (90)Y-ibritumomab tiuxetan and 18 who received (131)I-tositumomab. The percentage baseline at nadir and 4 wk post nadir and the time to nadir were selected as the toxicity indicators for both platelets and neutrophils. Multiple linear regression analysis was performed to identify significant predictors (P < 0.05) of each indicator.
RESULTS
For both platelets and neutrophils, pooled and separate analyses of (90)Y-ibritumomab tiuxetan and (131)I-tositumomab data yielded the time elapsed since the last chemotherapy as the only significant predictor of the percentage baseline at nadir. The extent of bone marrow involvement was not a significant factor in this study, possibly because of the short time elapsed since the last chemotherapy of the 7 patients with bone marrow involvement. Because both treatments were designed to deliver a comparable bone marrow dose, this factor also was not significant. None of the 14 factors considered was predictive of the time to nadir. The R(2) value for the model predicting percentage baseline at nadir was 0.60 for platelets and 0.40 for neutrophils. This model predicted the platelet and neutrophil toxicity grade to within ±1 for 28 and 30 of the 32 patients, respectively. For the 7 patients predicted with grade I thrombocytopenia, 6 of whom had actual grade I-II, dosing might be increased to improve treatment efficacy.
CONCLUSION
The elapsed time since the last chemotherapy can be used to predict hematologic toxicity and customize the current dosing method in radioimmunotherapy.
Topics: Adult; Aged; Aged, 80 and over; Algorithms; Antibodies, Monoclonal; Bone Marrow; Drug Resistance, Neoplasm; Female; Hematologic Diseases; Humans; Leukocyte Count; Linear Models; Lymphoma, Non-Hodgkin; Male; Middle Aged; Models, Statistical; Neutrophils; Platelet Count; Predictive Value of Tests; Radioimmunotherapy; Radiometry; Radiopharmaceuticals; Thrombocytopenia; Yttrium Radioisotopes
PubMed: 21098795
DOI: 10.2967/jnumed.110.079947 -
The Quarterly Journal of Nuclear... Dec 2006Optimization of therapy for individual patients remains a goal of clinical practice. Radionuclide imaging can identify those patients who may benefit from subsequent... (Review)
Review
Optimization of therapy for individual patients remains a goal of clinical practice. Radionuclide imaging can identify those patients who may benefit from subsequent targeted therapy by providing regional information on the distribution of the target. An ideal situation may be when the imaging and the therapeutic compounds are the same agent. Two antibodies ([ [90Y]ibritumomab, [131I]tositumomab) are now approved for the systemic radiotherapy of non-Hodgkin's lymphoma. The main hurdle is to deliver higher absorbed doses to the more refractory solid tumors paying particular regard to the bone marrow toxicity. The low dose is thought to be a result of the large size of antibodies slowing delivery to the target. Peptides having high affinity to receptors expressed on cancer cells are a promising alternative. They are usually rapidly excreted from the body through renal and/or hepatobiliary excretion thus creating a prolonged accumulation of the radioactivity in the kidneys, which represents a recognized issue for systemic radiotherapy. The first radiopeptide developed was a somatostatin analogue, which led to a major breakthrough in the field. Beside the kidney issue, somatostatin use remains limited to few cancers that express receptors in sufficiently large quantities, mainly neuroendocrine tumors. The gastrin releasing peptide (GRP) receptor is an attractive target for development of new radiopeptides with diagnostic and therapeutic potential. This is based upon the functional expression of GRP receptors in several of the more prevalent cancers including prostate, breast, and small cell lung cancer. This review covers the efforts currently underway to develop new and clinically promising GRP-receptor specific molecules labeled with imageable and therapeutic radionuclides.
Topics: Antibodies, Monoclonal; Drug Delivery Systems; Gastrin-Releasing Peptide; Humans; Lutetium; Neoplasms; Radioisotopes; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Bombesin
PubMed: 17043628
DOI: No ID Found -
The Lancet. Haematology Mar 2018Despite an abundance of therapeutic options, advanced-stage follicular lymphoma remains incurable. Furthermore, the ideal sequence and absolute benefit of post-induction...
BACKGROUND
Despite an abundance of therapeutic options, advanced-stage follicular lymphoma remains incurable. Furthermore, the ideal sequence and absolute benefit of post-induction therapy is unclear. We designed SWOG S0801 to assess the efficacy and safety of consolidative radioimmunotherapy and sequential maintenance rituximab following chemoimmunotherapy.
METHODS
For this single-arm, phase 2, multicentre study, we enrolled patients aged 18 years and older with a diagnosis of stage III, IV, or bulky stage II follicular lymphoma, grades 1, 2, or 3a, who had not received previous therapy, from from 20 institutions within the United States National Cancer Institute Clinical Trials Network. Patients were assigned to a 5-year treatment plan consisting of R-CHOP (rituximab plus cyclophosphamide [750 mg/m], doxorubicin [50 mg/m], vincristine [1·4 mg/m], and prednisone or prednisolone [100 mg]) every 21 days for up to six cycles, with rituximab 375 mg/m given on day 1 of cycles 1-4, followed by iodine tositumomab radioimmunotherapy and subsequent maintenance rituximab 375 mg/m within 12 weeks after the sixth cycle of R-CHOP, every 3 months for up to 4 years. The primary endpoint was 3-year progression-free survival in the intention-to-treat population. Efficacy and safety analyses were done in the intention-to-treat population and the per-protocol population. This trial was registered with ClinicalTrials.gov, number NCT00770224.
FINDINGS
Between April 1, 2009, and Dec 15, 2010, we enrolled 84 evaluable patients, of whom 73 completed R-CHOP and radioimmunotherapy. Of 69 patients who registered to maintenance therapy, only 41 completed the 4-year rituximab maintenance treatment. Progression-free survival at 3 years was 90% (95% CI 82-95). The most common grade 3 or worse adverse events included neutropenia in 48 (57%) patients, leucopenia in 34 (40%) patients, thrombocytopenia in 17 (20%) patients, and febrile neutropenia in 14 (17%) patients. Nine patients had possible treatment-related deaths during the study from secondary or unknown causes (n=3), cirrhosis (n=1), cardiac arrest (n=1), and secondary malignancies (n=4). Secondary malignancies occurred in seven patients, including two sarcomas, two colorectal carcinomas, two acute myelogenous leukaemias, and one case of renal-cell carcinoma.
INTERPRETATION
SWOG S0801 showed near universal responses following chemoimmunotherapy and radioimmunotherapy. However, most discontinuations occurred during maintenance therapy, suggesting that rituximab over a 4-year span is not feasible for many patients. Nonetheless, this sequential therapeutic strategy resulted in good overall outcomes for patients, including a low incidence of early disease progression.
FUNDING
The National Cancer Institute and GlaxoSmithKline.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Humans; Induction Chemotherapy; Lymphoma, Follicular; Maintenance Chemotherapy; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Positron-Emission Tomography; Prednisone; Radioimmunotherapy; Rituximab; Survival Analysis; Tomography, X-Ray Computed; Treatment Outcome; Vincristine
PubMed: 29396094
DOI: 10.1016/S2352-3026(18)30001-2 -
Journal of Nuclear Medicine Technology Dec 2006(131)I-Tositumomab has been used in treating patients with non-Hodgkin's lymphoma. It is generally recommended that high-energy collimators be used to image patients...
UNLABELLED
(131)I-Tositumomab has been used in treating patients with non-Hodgkin's lymphoma. It is generally recommended that high-energy collimators be used to image patients before they receive (131)I-tositumomab therapy, to determine the effective half-life for therapeutic dose and gross biodistribution. Because many nuclear medicine departments do not possess high-energy collimators, this study was designed to assess the suitability of using medium-energy collimators. The effect of scanning speed was also investigated, in an attempt to optimize the acquisition time.
METHODS
Measurements were taken using an elliptic anthropomorphic torso phantom and an organ-scanning phantom fitted with fillable spheres (1-5 cm in diameter) and organ inserts. Three phantom studies were performed with differing initial (131)I concentrations in the organs, the spheres, and the thoracic and abdominal chambers. Images were acquired with both high-energy and medium-energy collimators and at acquisition speeds of 20 and 100 cm/min. The half-life for each combination (study/collimator/speed) was calculated from a linear fit of the data. The contrast of the tumor sphere was assessed using 2 identical regions, placed on and beside the sphere, and averaged over several time points. Biodistribution and image quality were visually assessed by 2 independent observers.
RESULTS
Measured half-life values and visual assessment of biodistribution showed no significant difference between the 2 collimators (P = 0.32) or acquisition speeds (P = 0.85). A significant difference in the contrast of the tumor spheres was observed between the 2 collimators (P < 0.01) but not between acquisition speeds. Visual assessment of the images showed increased noise on the image acquired at 100 cm/min, although this noise did not affect lesion detectability.
CONCLUSION
Measured half-life is not significantly different between the 2 collimators; hence, calculation of the residence time would be nearly the same. Medium-energy collimators can be used to accurately calculate the (131)I-tositumomab therapeutic dose and detect alterations in biodistribution.
Topics: Antibodies, Monoclonal; Body Burden; Humans; Image Interpretation, Computer-Assisted; Lymphoma, Non-Hodgkin; Metabolic Clearance Rate; Organ Specificity; Phantoms, Imaging; Radiopharmaceuticals; Relative Biological Effectiveness; Time Factors; Tissue Distribution; Tomography, Emission-Computed, Single-Photon; Whole Body Imaging; Whole-Body Counting
PubMed: 17146111
DOI: No ID Found -
European Journal of Nuclear Medicine... May 2011Improved data collection methods have improved absorbed dose estimation by tracking activity distributions and tumor extent at multiple time points, allowing... (Clinical Trial)
Clinical Trial
PURPOSE
Improved data collection methods have improved absorbed dose estimation by tracking activity distributions and tumor extent at multiple time points, allowing individualized absorbed dose estimation. Treatment with tositumomab and (131)I-tositumomab anti-CD20 radioimmunotherapy (BEXXAR) yields a cold antibody antitumor response (cold protein effect) and a radiation response. Biologically effective contributions, including the cold protein effect, are included in an equivalent biological effect model that was fit to patient data.
METHODS
Fifty-seven tumors in 19 patients were followed using 6 single proton emission computed tomography (SPECT)/CT studies, 3 each post tracer (5 mCi) and therapy (∼100 mCi) injections with tositumomab and (131)I-tositumomab. Both injections used identical antibody mass, a flood dose of 450 mg plus 35 mg of (131)I tagged antibody. The SPECT/CT data were used to calculate absorbed dose rate distributions and tumor and whole-body time-activity curves, yielding a space-time dependent absorbed dose rate description for each tumor. Tumor volume outlines on CT were used to derive the time dependence of tumor size for tracer and therapy time points. A combination of an equivalent biological effect model and an inactivated cell clearance model was used to fit absorbed dose sensitivity and cold effect sensitivity parameters to tumor shrinkage data, from which equivalent therapy values were calculated.
RESULTS
Patient responses were categorized into three groups: standard radiation sensitivity with no cold effect (7 patients), standard radiation sensitivity with cold effect (11 patients), and high radiation sensitivity with cold effect (1 patient).
CONCLUSION
Fit parameters can be used to categorize patient response, implying a potential predictive capability.
Topics: Antibodies, Monoclonal; Humans; Iodine Radioisotopes; Lymphoma, Non-Hodgkin; Models, Biological; Radioimmunotherapy; Treatment Failure; Tumor Burden
PubMed: 21174088
DOI: 10.1007/s00259-010-1699-3 -
PloS One 2014The sensitivity of human Burkitt's lymphoma cells to rituximab (Rtx) and tositumomab (Tst) was assessed on cells expressing different levels of CD20 on surface. Cells...
BACKGROUND
The sensitivity of human Burkitt's lymphoma cells to rituximab (Rtx) and tositumomab (Tst) was assessed on cells expressing different levels of CD20 on surface. Cells that harbor low CD20 levels may resists against therapeutics response to CD20-specific antibodies. We postulated that, radiation-induced modulation of CD20 surface levels may play a crucial and central role in determining the relative efficacy of rituximab and tositumomab in treating Burkitt's lymphoma disease. Here, we examined the γ-radiation-induced CD20 expression in the Burkitt lymphoma cell line 'Daudi' and the relation of differential levels of CD20 with anti-CD20 mAbs mediated cell death.
METHODOLOGY
In this study we examined kinetics of CD20 expression following sub lethal doses ofγ-radiation to Daudi cells and thereafter anti-CD20 mAbs (rituximab and tositumomab) were added in cell suspensions. The correlation of kinetics of CD20 expression and cells treated with anti-CD20 mAbs/or corresponding isotype Abs with special reference to changes in mitochondrial membrane potential and reactive oxygen species generation was also examined. Further, we also investigated the efficacy of anti-CD20 mAbs and possible induction of cell death in relation to levels of CD20 cell surface expression.
CONCLUSION
This report provides evidence that CD20 expression can be induced by exposure of cells to γ-radiation. In addition, these findings demonstrated that the efficacy of anti-CD20 mAbs is dependent on the surface levels of CD20. Based on these findings, we hypothesized (i) irradiation just prior to immunotherapy may provide new treatment options even in aggressive B cell tumors, which are resistant to current therapies in vivo (ii) The efficacy of induction of apoptosis varies with type of monoclonal antibodies in vitro.
Topics: Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Antineoplastic Agents; Cell Cycle; Cell Death; Cell Line, Tumor; Cell Membrane; Gene Expression; Humans; Immunophenotyping; Membrane Potential, Mitochondrial; Reactive Oxygen Species; Rituximab
PubMed: 25364827
DOI: 10.1371/journal.pone.0111113 -
Journal of Nuclear Medicine Technology Sep 2007Residence time measurements obtained by serial whole-body conjugate-view imaging are commonly used in patient-specific dosimetry for radioimmunotherapy applications. In... (Comparative Study)
Comparative Study
UNLABELLED
Residence time measurements obtained by serial whole-body conjugate-view imaging are commonly used in patient-specific dosimetry for radioimmunotherapy applications. In order to determine the effect of collimator selection on residence time measurements for (131)I, the accuracies of (131)I half-life measurements obtained with multiple gamma-camera and collimator combinations were investigated.
METHODS
Serial anterior and posterior whole-body images were acquired over a period of 15 d with 4 different gamma-cameras and medium- or high-energy collimators. Background-corrected geometric mean counts from the images were fitted to a monoexponential curve to determine the half-life of (131)I obtained with the different gamma-camera and collimator combinations.
RESULTS
An average half-life of 8.15 d (SD, 0.07 d) was obtained with all gamma-camera and collimator combinations. A half-life of 8.12 d (SD, 0.11 d) was obtained with the high-energy collimators, and a half-life of 8.18 d (SD, 0.04 d) was obtained with the medium-energy collimators. These values are all very close to the (131)I physical half-life of 8.02 d and were not found to be statistically significantly different (P = 0.44). Similar results were obtained for the half-life obtained with single-head gamma-camera configurations (mean half-life, 8.15 d; SD, 0.12 d). The therapeutic (131)I-tositumomab dose resulting from the differences in the measured half-life ranged from 2.58 to 2.6 GBq (69.8-70.4 mCi).
CONCLUSION
There is no significant difference in (131)I half-life and residence time measurements obtained with medium- or high-energy collimators in dual-head or single-head imaging configurations.
Topics: Antibodies, Monoclonal; Equipment Design; Equipment Failure Analysis; Radiopharmaceuticals; Radiotherapy Dosage; Reproducibility of Results; Sensitivity and Specificity; Whole-Body Counting
PubMed: 17823454
DOI: 10.2967/jnmt.106.038174 -
Journal of Clinical and Experimental... Nov 2007Radioimmunotherapy (RIT) treatment for lymphoma is a novel targeted therapeutic approach. Several years of development of radioimmunotherapeutic compounds came to... (Review)
Review
Radioimmunotherapy (RIT) treatment for lymphoma is a novel targeted therapeutic approach. Several years of development of radioimmunotherapeutic compounds came to fruition in February of 2002 when (90)Y-ibritumomab tiuxetan (Zevalin, Y2B8) was approved in the USA and later in Europe, for the treatment of relapsed or refractory, low grade or transformed B-cell lymphoma. (90)Y-ibritumomab tiuxetan utilizes a monoclonal anti-CD20 antibody to deliver beta-emitting yttium-90 to the malignant B-cells. Clinical trials have demonstrated its efficacy, which is largely independent of the intrinsic activity of the anti-CD20 antibody. A similar anti-CD20 radiotherapeutic compound, (131)I-tositumomab, was subsequently approved in the USA. The advantages of increased efficacy compared to the naked antibody are gained at the expense of myelotoxicity which is dose limiting but reversible. Studies exploring expanded applications of radioimmunotherapy have been recently completed or are under way. It is hoped that RIT will be an ideal agent for consolidation after chemotherapy for both indolent and aggressive non-Hodgkin lymphoma as well as a useful addition to preparatory high dose regimens prior to transplant. RIT has been shown to be an effective and clinically relevant complementary therapeutic approach for patients with lymphoma.
Topics: Clinical Trials as Topic; Humans; Lymphoma, Non-Hodgkin; Radioimmunotherapy
PubMed: 18040144
DOI: 10.3960/jslrt.47.43 -
BMC Cancer Dec 2020The purpose of this network meta-analysis of randomized controlled trials (RCTs) was to compare rank targeted therapies for patients with diffuse large B-cell lymphoma... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The purpose of this network meta-analysis of randomized controlled trials (RCTs) was to compare rank targeted therapies for patients with diffuse large B-cell lymphoma (DLBCL).
METHODS
The PubMed, EmBase, and Cochrane library electronic databases were systematically searched throughout December 2019. Direct and indirect evidence from relevant RCTs was identified for network meta-analysis. The pooled results for grade 3 or greater adverse events between targeted therapies and chemotherapy were calculated using a random-effects model.
RESULTS
A total of 18 RCTs enrolling 8207 DLBCL patients were selected for the final meta-analysis. The results of the network analysis indicated that the addition of dacetuzumab (74.8%) to rituximab-based regimens or lenalidomide (77.1%) was associated with better therapeutic effects on overall survival, whereas dacetuzumab (80.4%) or bortezomib (70.8%) added to rituximab was most likely to improve events-free survival. Moreover, lenalidomide (93.8%) and I-tositumomab (77.2%) were associated with higher overall response rates. Finally, patients receiving targeted therapies were associated with an increased risk of diarrhea (RR: 2.63; 95%CI: 1.18-5.86; P = 0.019), and thrombocytopenia (RR: 1.41; 95%CI: 1.05-1.90; P = 0.023).
CONCLUSIONS
This study provides the best treatment strategy for DLBCL patients in terms of overall survival, events-free survival, and overall response rate. The findings of this study require validation with further large-scale RCTs.
Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Humans; Lymphoma, Large B-Cell, Diffuse; Molecular Targeted Therapy; Prognosis; Survival Rate
PubMed: 33308179
DOI: 10.1186/s12885-020-07715-2